Lower alkyl-ib-o-auphatic desermdates



United States Patent The present invention concerns 3-epi-allo-yohimbane compounds having the nucleus of the formula:

More particularly, it relates to IS-etherified hydroxy-3-epiallo-yohimbane l6-carboxylic acid esters, salts, N-oxides or salts of N-oxides of such compounds. Apart from the groups in the 16-position and in the 18-position, the compounds of the present invention may contain additional substituents. For example, a cyano group, or more espectially a lower alkoxy group may be attached to the l7-position having preferably the a-configuration. Other substituents, preferably attached to the positions of the aromatic nucleus, i.e., ring A, of the molecule, which are available for substitution, more specifically to the 9-position, the 10-position, the ll-position and/or the l2-position, are represented, for example, by aliphatic hydrocarbon, such as lower alkyl and the like, etherified hydroxyl, such as lower alkoxy, cycloalkyloxy, cycloalkyl-lower alkoxy, carbocyclic aryloxy, carbocyclic aryl-lower alkoxy, lower alkylene dioxy and the like, esterified hydroxyl, such as lower alkoxy-carbonyloxy, lower alkanoyloxy, halogeno and the like, etherified mercapto, such as lower alkylmercapto and the like, nitro, amino, such as N,N-disubstituted amino and the like, substituted aliphatic hydrocarbon, such as substituted lower alkyl, for example, halogeno-lower alkyl, particularly trifluoromethyl, or any other suitable substituent. Other substituents, particularly aliphatic hydrocarbon radicals, such as lower alkyl, may also be attached to positions of other nuclei, particularly of the heterocyclic nucleus C, more specifically to the 5- position and/ or the 6-position.

More especially, the invention is directed to compounds of the formula:

aizaaae Patented Mar. 24, 1954 kenyl, lower alkynyl, cycloalkyl, cycloalkenyl and the like, a substituted aliphatic radical, containing, for example, cycloalkyl, carbocyclic aryl, e.g. phenyl and the like, hydroxyl, etherified hydroxyl, e.g. lower alkoxy and the like, esterified hydroxyl, e.g. lower alkoxy-carbonyloxy, lower alkanoyloxy, carbocyclic aryl-carbonyloxy, carbocyclic aryl-lower aliphatic hydrocarbon-carbonyloxy, halogeno and the like, acyl, e.g. lower alkanoyl, carbolower alkoxy and the like, etherified mercapto, e.g. lower alkyl-mercapto and the like, tertiary amino, e.g. N,N-di lower alkyl-amino and the like, a heterocyclic, particularly a monocyclic heterocyclic, radical or any other analogous group as substituents suitable for being attached to an aliphatic radical, or carbocyclic aryl, e.g. monocyclic carbocyclic aryl and the like, each of the radicals R R and R stands for hydrogen, aliphatic hydrocarbon, particularly lower alkyl, substituted aliphatic hydrocarbon, particularly substituted lower alkyl, such as halogeno-lower alkyl, especially trifluoromethyl, etherified hydroxyl, particularly lower alkoxy, as well as cycloalkyloxy, cycloalkyl-lower alkoxy, carbocyclic aryloxy, carbocyclic aryl-lower alkoxy or any other analogous etherified hydroxy group, esterified hydroxyl, particularly halogeno, as well as lower alkoxy-carbonyloxy, lower alkanoyloxy and the like, etherified mercapto, particularly lower alkyl-mercapto, nitro, amino, e.g. N,N-di-substituted amino and the like, or, whenever two of the groups R R and R are attached to two adjacent positions and taken together, for lower alkylene dioxy, and R attached to one of the positions 5 and 6, stands for hydrogen or lower alkyl, salts, N-oxides or salts of N-oxides of such compounds, as well as process for the preparation of such compounds.

The invention is also directed to compounds of the formula:

in which each of the groups R R R R R R and R have the previously given meaning, salts, N-oxides or salts of N-oxides thereof, as well as process for the preparation of such compounds.

The radical of the alcohol portion of the ester grouping attached to the 16-position of the molecule, which in the above formulae, is represented by the group R stands above all for lower alkyl containing from one to seven, preferably from one to four, carbon atoms; such groups are particularly methyl, ethyl, n-propyl, isoproyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, as well as n-pentyl, isopentyl, n-hexyl, n-heptyl and the like.

The esterifying portion of the ester grouping attached to the l6-position of the molecule, represented, for example, by the radical R in the above formulae, may also stand for substituted lower alkyl, such as, for example, monocyclic carbocyclic aryl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, such as phenyl-lower alkyl, e.g. benzyl, l-phenyl-ethyl, 2-phenylethyl and the like, or phenyl-lower alkyl, in which phenyl is substituted by lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, or any other suitable substituent.

Other substituted lower alkyl radicals, as represented, for example, by the group R in the above formulae, are,

for example, lower alkyl radicals substituted by functional groups, such as etherified hydroxy, particularly lower alkoxy containing preferably from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, tertiary amino, such as N,N- di-lower alkyl-amino, in which lower alkyl contains from one to four carbon atoms, e.g. N,N-dimethylamino, N- ethyl-N-methylamino, N,N-dicthylamino, N,N-di-n-propylamino, N,N-di-isopropylamino and the like, as well as l-N,N-lower alkylene-imino, in which lower alkylene contains from four to six ring carbon atoms, e.g. l-pyrrolidino, l-piperidino, 1-N,N-hexamethyleneimino and the like, l-N,N-lower oxa-alkylene-imino, in which lower oxa-alkylene contains preferably four ring carbon atoms, e.g. 4-morpholino and the like, or 1-N,N-lower aza-alkylene-imino, in which lower aza-alkylene contains from four to six ring carbon atoms, particularly 4-lower alkyll-piperazino, e.g. 4-methyl-1-piperazino, 4-ethyl-1-piperazino and the like. The lower alkyl portion in a lower alkyl radical, substituted by functional groups, as represented, for example, by etherified hydroxy-lower alkyl, tertiary amino-lower alkyl and the like, may be represented by a lower alkylene radical, which contains from two to four carbon atoms, and separates the described substituent, such as etherified hydroxyl, tertiary amino and the like, from the carbon atom of the carboxy group by at least two carbon atoms. Preferably, such lower alkylene radical contains from two to three carbon atoms and separates the substituent, such as the etherified hydroxyl group and the like, from the carboxy group by the same number of carbon atoms. The alkylene radicals are primarily 1,2-ethylene, l-methyl-1,2-ethylene, 2- methyl-l,2-ethylene, l,3-propylene, 1,4-butylene and the like. Lower alkyl radicals containing a functional group, which radicals are represented by R in the above formulae, may be, for example, 2-lower alkoxy-ethyl, e.g. 2-methoxyethyl, 2-ethoxyethyl and the like, 2-lower alkoxy-propyl, e.g. Z-methoxypropyl and the like, 3-lower alkoxy-propyl, e.g. 3-methoxypropyl, 3-ethoxypropyl and the like, 2-N,N-di-lower alkyl-ethyl, e.g. 2-N,N-dimethylaminoethyl, 2-N,N-diethylaminoethyl and the like, 2- lflN-di-lower alkyl-amino-propyl, e.g. 2-N,N-dimethylaminopropyl and the like, 3-N,N-di-lower alkyl-aminopropyl, e.g. 3-N,N-di-rnethyl-arrunopropyl, 3-N,N-diethylaminopropyl and the like, 2-(1-N,N-lower alkyleneimino)-ethyl, e.g. 2-(l-pyrrolidino)-ethyl, 2-(l-piperidino)-ethyl and the like, 3-(1-N,N-lower alkyleneimino)- propyl, e.g. 3-(l-piperidino)-propyl and the like.

The substituent attached to the 17-position, as represented by the group R in the above formulae, may stand for cyano. It primarily represents lower alkoxy which contains preferably from one to four carbon atoms, and stands for ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, but above all for methoxy.

The etherified hydroxyl group attached to the l8-position and represented, for example, by the grouping R in the previously given formulae, is preferably etherified by an aliphatic radical. The latter, represented in the above formula by the group R stands, above all, for lower alkyl, containing from one to ten, preferably from one to seven, carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-hcptyl and the like.

Other etherified l8-hydroxyl groups have as the etherifying portions, represented, for example, by the radical R in the above-given formulae, other aliphatic radicals, such as, for example, lower alkenyl, particularly lower allylic alkenyl, containing preferably from three to five carbon atoms, e.g. allyl, Z-methyl-allyl, 2-butenyl, 3-methyl-2-butenyl, Z-pentenyl and the like, lower alkynyl, e.g. propargyl and the like, or cycle-aliphatic radicals, such as cycloalkyl containing from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentyl or cyclohexyl, as well as cyclopropyl, cycloheptyl, cyclooctyl and the like, or cycloalkenyl, containing preferably from five to six ring carbon atoms, e.g. 3-cyclopentenyl, 2-cyclohexenyl and the like.

Aliphatic radicals etherifying the IS-hydroxyl group, as represented by R in the above formulae, may contain substituents, such as, for example, cycloaliphatic radicals. Resulting substituted aliphatic radicals may be represented by cycloaliphatic-aliphatic radicals, for example, by cycloalkyl-lower alkyl, in which cycloalkyl contains from three to eight, especially from five to six, ring carbon atoms, and lower alkyl contains from one to four carbon atoms, e.g. cyclopentylmethyl, l-cyclopentylethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl and the like, cycloalkyl-lower alkenyl, in which cycloalkyl has the above-given meaning and lower alkenyl contains preferably from three to five carbon atoms, e.g. 3-cyclopentyl-allyl and the like.

Other substituted aliphatic radicals contain as substituents carbocyclic aryl groups and represent, for example, carbocyclic aryl aliphatic radicals, such as monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lowcr alkyl, e.g. benzyl, diphenylmethyl, l-phenylethyl, 2-phenylethyl and the like, as Well as carbocyclic-lower alkenyl, such as monocyclic carbocyclic aryl-lower alkenyl, particularly phenyl-lower alkenyl, e.g. 3-phenylallyl and the like, and analogous radicals, in which the carbocyclic aryl nucleus is substituted, by one or more than one of the same or different substituents, for example, by lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkenyloxy, e.g. allyloxy and the like, halogeno, e.g. fiuoro, chloro, bromo and the like, lower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, halogeno-lower alkyl, e.g. trifiuoromethyl and the like, nitro, amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino and the like, or any other suitable substituent.

Other substituted aliphatic radicals, particularly lower alkyl groups, represented in the above formulae by the group R may be substituted by functional groups, such as hydroxyl or etherified hydroxyl. Aliphatic radicals containing such substituents are, for example, hydroxy-aliphatic radicals, such as hydroxy-lower alkyl, e.g. 2-hydroxy-ethyl, Z-hydroxy-propyl and the like, or etherified hydroxy-aliphatic radicals, such as lower alkoxy-lower alkyl, in which lower alkoxy contains from one to four carbon atoms, and stands, for example, for methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, which lower alkoxy-lower alkyl groups may be represented by 2-lower alkoxy-ethyl, e.g. Z-methoxyethyl, Z-ethoxyethyl and the like, 2-lower alkoxy-propyl, e.g. Z-methoxy propyl, 2-ethoxypropyl and the like, 3-lower alkoxypropyl, e.g. 3-methoxypropyl, 3-ethoxypropyl and the like. Other etherified hydroxyl groups, which may substitute aliphatic, particularly lower alkyl, radicals are, for example, lower alkenyloxy, e.g. allyloxy and the like, cycloalkyloxy, e.g.

cyclopentyloxy, cyclohexyloxy and the like, ccloalkenyloxy, e.g. 3-cyclohexenyl and the like, cycloalkyl-lower alkoxy, e.g. cyclopentylmethyloxy, 2-cyclohexylethyloxy and the like.

Additional substituted aliphatic, especially substituted lower alkyl, radicals contain as substituents, esterified hydroxyl groups, such as lower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, lower alkanoyloxy, e.g. acetoxy, propionyloxy and the like, carbocyclic aryl-carbonyloxy, particularly monocyclic carbocyclic aryl-carbonyloxy, e.g. benzoyloxy, and benzoyloxy in which the carbocyclic aryl portion is substituted in one or more than one position by substituents, such as, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkenyloxy, e.g. allyloxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, lower alkoxycarbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, halogcno lower alkyl, e.g. trifluoromethyl and the like, nitro, amino, such as N,N-di-lowcr alkyl-amino, e.g. N,N-dimethylamino and the like, or any other suitable substituents, carbocyclic aryl-lower aliphatic hydrocarbon-carbonyloxy, such as monocyclic carbocyclic aryl-lower alkanoyloxy or monocyclic carbocyclic aryl-lower alkenoyloxy, e.g. phenylacetoxy, 3- phenylpropionyloxy, cinnamoyloxy and the like and these radicals substituted in the carbocyclic nucleus by one or more than one of the same or of different substituents, such as those mentioned hereinbefore, or halogeno (representing a hydroxyl group esterified with a hydrohal-ic acid), e.g. fluoro and the like. Aliphatic, particularly lower alkyl, radicals containing esterified hydroxyl groups are, for example,

2-lower alkoxy-carbonyloxy-ethyl,

e.g. Z-methoxy-carbonyloXy-ethyl and the like,

2-lower alkanoyloxy-ethyl,

e.g. Z-acetylethyl,

2-propionyl-ethyl and the like,

2-monocyclic carbocyclic aryl-carbonyloxy-ethyl,

e.g. 2-benzoyloxy-ethyl,

2-( 3 ,4,5-trimethoxy-benzoyl) -ethyl,

2-(4-ethoxycarbonyl-syringoyloxy)-ethyl and the like,

2-(monocyclic carbocyclic aryl-lower alkanoyloxy)-ethyl,

e. g. 2- [3 3 ,4,5-trimethoxy-phenyl -propi0nyloxy] -ethyland the like,

Z-(monocyclic carboeyclic aryl-lower alkenoyloxy)-ethyl,

e.g. Z-cinnamoyloxy-ethyl and the like,

halogeno-lower alkyl,

e.g. Z-trifiuoroethyl and the like,

or the corresponding 2-esterified hydroxypropyl, 3-esteritied lhydroxy-propyl groups and the like.

Other aliphatic radicals etherifying the l8-hydr0xyl group and represented, for example, by R in the above formulae, are substituted, for example, by acyl, particularly lower alkanoyl, e.g. acetyl, propionyl and the like, or carbo-lower alkoxy, e.g. carbomethoxy, carboethoxy and the like, etherified mercapto, such as lower alkylmercapto, e.g, methylmercapto, ethylmercapto and the like, amino, particularly tertiary amino, such as N,N- di-lower alkyl-amino, e.g. N,N-dimethylamino, N-ethyl- N-methyl-amino, N,l l-diethylamin'o, N,N-di-n-propylamino, N,N-di-isop1'opylamino, N,N-dibutylamino and the like, N,N-lower alkyleneimino, in which alkylene contains from four to six carbon atoms, e.g. l-pyrrolidino, l-piperidino, 1-N,N-hexamethyleneimino and the like, N,N-lower oxa-alkylene-imino, in which alkylene contains, primarily, four carbon atoms, e.g. 4-morpholino and the like, N,N-lower aza-alkylene-imino, in which alkylene contains from four to six ring carbon atoms, particularly 4-lower alkyl-l-piperazino, e.g. 4-methyl-lpiperazino, 4-ethyl-l-piperazino and the like, or any other functional group suitable for being attached to an aliphatic hydrocarbon radical. Such substituted aliphatic radicals are, therefore, primarily lower alkanoyl-lower alkyl, e.g. acetylmethyl, propionylmethyl and the like, carbo-lower alkoxy-lower dkyl, e.g. carbomethoxymethyl, oarbethoxymethyl and the like, lower alkyl-mercapto-lower alkyl, e.g. methyl-mercapto-methyl, Z-ethylmercapto-ethyl and the like, tertiary amino-lower alkyl, such 2-N,N-cli-lower alkyl-amino-ethyl,

e.g. 2-N,N-dimethylaminoethyl, 2-N,N-diethyl-aminoethyl and the like, 2N,N-di-lower alkyl-amino propyl, e.g. 2-N,N-dimethylaminopropyl, 2-N,N-diethylamin0propyl and the like, 3-N,N-di-lower alkyl-amino-propyl, e.g. 3-N,N-dimethylarninopropyl, 3-N,N-diethylaminopropyland the like, 2-N,N-lower alkylene-imino-ethyl,

e. g. 2-( l-pyrrolidino) -ethyl, 2-(1-piperidino)-ethyl and the like, 3-N,N-lower alkylene-imino-propyl,

e. g. 3 l-pyrrolidino) -propyl,

6 3-(l-piperidino) -propy1 and the like, 2-(4-l0wer alkyl-l-piperazino) -ethyl, e.g. 2-(4-methyl-l-piperazino)-ethyl, 2-(4-ethyl-1-piperazino)-ethyl and the like, 3 (4-lower alkyl- 1 -piperazino) -propyl, e.g. 3-(4-methyl-l-piperazino)-propyl, 3-(4-ethyl-l-piperazino)-propyl and the like, as well as other analogous aliphatic radicals substituted by functional groups.

Aliphatic radicals may also contain heterocyclic groups as substituents. Such groups are, for example, monocyclic heterocyclic aryl groups, such as pyridyl, e.g. 2- pyridyl, 4-pyridyl and the like, thienyl, e.g. 2-thienyl and the like, monocyclic heterocyclic aliphatic groups, such as tetrahydrofunanyl, e.g. Z-tetrahydrofuranyl and the like. These substituted aliphatic radicals may be represented, for example, by pyridyl-lower alkyl, e.g. 2-pyridylrnethyl and the like, tetrahydrofuranyl-lower alkyl, e.g. 2-tetrahydrofuranylrnethyl and the like.

Etherifying groups in an l8-etherified hydroxyl group, such as in a group of the formula R -O in the above formulae, may also be represented by carbocyclic aryl groups, particularly monocyclic carbocyclic aryl, such as phenyl and phenyl substituted by one or more than one of the same of different substituents, such as lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkenyloxy, e.g. allyloxy and the like, halogeno, e.g. fiuoro, chloro, bromo and the like, the lower alkoxy-carbonyloxy, e.g. methoxy-carbonyloxy, ethoxy-carbonyloxy and the like, halogeno-lower alkyl, e.g. trifluoromethyl and the like, nitro, amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino and the like or any other suitable substituents. These carbocyclic aryl radicals etherifying the 18-hydroxyl group may be represented, for example, by phenyl, 3-methyl-phenyl, 4-methoxy-phenyl, 3,4,5-trimethoxy-phenyl, 3,4-dichlorophenyl, 4-bromo-phenyl, O-ethoxycarbonyl-syringoyl, 3- N,N-dimethylamino-phenyl and the like.

Substituents attached to any of the positions available for substitution in ring A, particularly those represented by the groups R R and R (each of which may also stand for hydrogen) in the previously given formulae, may be, for example, lower aliphatic hydrocarbon, especially lower-alkyl, containing preferably from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, or functional groups, such as, for example, etherified hydroxyl, particularly lower alkoxy, containing preferably from one to four carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, as well as cycloalkyloxy, in which cycloalkyl contains from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentyloxy, cyclohexyloxy and the like, cycloalkyl-lower alkoxy, in which cycloalkyl contains from three to eight, preferably from five to six, ring carbon atoms, e.g. cyclopentylmethoxy, 2-cyclopentylethoxy, cyclohexylmethoxy and the like, carbocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g. phenyloxy and the like, carbocyclic aryl-lower alkoxy, such as monocyclic carbocyclic aryl-lower alkoxy, for example, phenyl-lower alkoxy, e.g. benzyloxy, diphenylmethoxy, 2-phenylethoxy and the like, esterified hydroxyl, particularly lower alkoxy-carbonyloxy, e.g. methoxycarbonyloxy, ethoxycarbonyloxy and the like, or lower alkanoyloxy, e.g. acetoxy, propionyloxy and the like, etherified mercapto, particularly lower alkyl-mercapto, containing preferably from one to four carbon atoms, e.g. methylmercapto, ethylmercapto and the like, nitro, amino, particularly N,N-disubstituted amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N-ethyl-N-methylamino, N,N-diethylarnino and the like, halogeno, e.g. fiuoro, chloro, bromo, iodo and the like, halogeno-lower alkyl, particularly trifluoromethyl and the like, or any other suitable functional group. A substituent may also be attached to two adjacent positions of ring A and form a fused-on ring; for example, two of the radicals R R and R in the formulae, when substituting two neighboring positions and taken together, may also form a fused-on cyclic substituent. Such substituents may be represented, for example, by lower alkylene-dioxy, e.g. methylenedioxy, 1,1-ethylenedioxy and the like, or any other analogous grouping.

Substituents, which may be attached to other positions in the molecule, particularly to positions in ring C, which are available for substitution, are primarily aliphatic hydrocarbon, such as lower alkyl, containing preferably from one to four carbon atoms, particularly methyl, as well as ethyl, n-propyl, isopropyl and the like. The radi cal R in the previously given formulae, which stands primarily for hydrogen, may, therefore, also represent lower alkyl, particularly methyl, as well as ethyl and the like.

Salts of the compounds of this invention are primarily therapeutically acceptable acid addition salts, particularly those with inorganic acids, such as mineral acids, e.g. hydrochloride, hydrobromic, sulfuric, phosphoric acids and the like, as well as with organic acids, eg acetic, tartaric, methane sulfonic acid and the lik Also included within the scope of the present invention are the N-oxides of the above-mentioned compounds, as well as the therapeutically acceptable acid addition salts of these N-oxides, such as the addition salts with the above-mentioned inorganic, particularly mineral, and organic acids.

In view of the fact that several asymmetric carbon atoms are present in the compounds of this invention, the latter may be obtained in the form of a mixture of racemates, racemates or optically pure compounds.

The compounds of the present invention have sedative and tranquilizing effects on the central nervous system; some of them also show antihypertensive properties. Compared with the antihypertensive and sedative effe t of naturally occurring Rauwolfia alkaloids, such as, for example, reserpine, deserpidine, rescinnamine and the like, the compounds of this invention generally appear to have more predominant sedative effects accompanied by negligible antihypertensive activities.

Furthermore, it has also been found that, contrary to the naturally occurring compounds, which show a slow onset of pharmacological action and an often uncontrollably long-lasting effect, the compounds of this invention act quickly and the activity is of definite duration, thus making the recovery after treatment more complete and easily controllable. It has also been found that the therapeutically acceptable salts, particularly those with mineral acids, e.g. hydrochloric acid and the like, of these compounds are to a high degree water-soluble, and are, therefore, extremely useful in the preparation of pharmaceutical compositions, particularly of aqeuous solutions for injection and aqueous oral preparations, e.g. elixirs and the like.

The compounds of the present invention can, therefore, be used primarily as sedative and tranquilizing agents to relieve states of hyperactivity, tension and agitation, as, for example, associated with mental disturbances, anxiety and the like. Certain of the above-described compounds may also be used as antihypertensive compounds to counteract hypertensive conditions, such as, for example, renal hypertension, toxemia and the like.

Furthermore, the compounds of this invention are suitable in calming laboratory test animals, such as monkeys, cats and the like, as well as in the Veterinary field to quiet animals, particularly chickens, turkeys and the like, as well as other domestic animals to facilitate handling during vaccination, shipment and the like.

In addition the compounds of this invention have shown strong antifibrillatory effects, which are particularly pronounced in compounds containing an ldot-etherified hydroxyl group, i.e. compounds of the l8-epi-series. These compounds are, therefore, suitable in the treatment of 8 cardiac irregularities, including extrasystoles, auricular fibrillation and the like.

A preferred group of compounds having the abovegiven properties is represented by the formula:

in which each of the groups R and R represents lower alkyl, containing preferably from one to seven carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl and the like, and R represents lower alkoxy containing from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, whereby R is preferably attached to the 10-position or the ll-position, therapeutically acceptable acid addition salts, N-oxides or a therapeutically acceptable acid addition salts of N-oxides thereof.

These compounds are represented by the lower alkyl 18-O-lower alkyl-reserpates, in which lower alkyl contains from one to four carbon atoms, and is represented by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, therapeutically acceptable acid addition salts, N-oxides or therapeutically acceptable acid addition salts of N-oxides thereof. These compounds have pronounced sedative and tranquilizing effects of fast onset and easily controllable duration, accompanied by negligible antihypertensive properties and may be represented by methyl 18-O-methyl-reserpate, methyl 18-O-ethyl-reserpate, methyl l8-O-n-propyl-reserpate, methyl 18-O-isopropyl-reserpate, methyl l8-O-n-butyl reserpate, methyl 18-O-n-pentyl-reserpate, ethyl IS-O-methyl-reserpate, ethyl 18-O-ethyl-reserpate,

ethyl 18-O-n-propyl-reserpate, ethyl l8-O-n-butyl-reserpate, n-propyl 18-O-methyl-reserpate, n-propyl l8-O-ethyl-reserpate, isopropyl 18-O-methyl-reserpate, isopropyl 18-O-n-propyl-reserpate, n-butyl IS-O-methyl-reserpate, n-butyl IS-O-ethyl-reserpate, isobutyl l8-O-methyl-reserpate, n-pentyl 18-O-methyl-reserpate, n-hexyl l8-O-methyl-reserpate and the like, or therapeutically acceptable acid addition salts of these compounds, such as the hydrochlorides and the like.

Other compounds having the aforementioned formula are, for example, lower alkyl 18-O-lower alkyl-9-methoxy-deserpidates, e.g. methyl 9-methoxy 18 O-methyldeserpidate, methyl l8-O-ethyl 9 methoxy deserpidate, methyl 9-methoxy 18 O-n-propyl-deserpidate, ethyl 9- methoxy-18-O-methyl-deserpidate and the like, lower alkyl 18-O-lower alkyl-10-methoxy-deserpidates, e.g. methyl l0- methoxyl 8-Omethyl-dcserpidate, methyl 1 S-O-ethyll 0- methoXy-deserpidate, methyl lO-methoxy-l8-O-n-propyldeserpidate, ethyl IO-methoxy-IS-O-methyl-deserpidate, npropyl 10-rnethoxy 18 O-methyl-deserpidate, isopropyl lO-methoxy-lS-O-methyl-deserpidate and the like, lower alkyl 11-ethoxy-18-O-lower alkyl-deserpidates, e.g. methyl 1l-ethoxy-lS-O-methyl-deserpidate, methyl l1-ethoxy-l8- O-ethyl-deserpidate and the like, lower alkyl 18-O-lower alkyl-11-n-propyloxy-deserpidates, e. g. methyl IS-O-methyl-ll-n-propyloxy-deserpidate, methyl l8-O-ethyl l1 npropyloxy-deserpidate and the like, lower alkyl ll-isopropyloxy-18-O-lower alkyl-deserpidates, e.g. methyl ll-isopropyloxy-l8-O-methyl-deserpidate, ethyl 11 -isopropyloxy-18-O-methyl-deserpidate and the like, lower alkyl 11- n-butyloxy-lS-O-lower alkyl-deserpidates, e.g. methyl l1- n-butyloxy-l8-O-methyl-deserpidate, methyl 11 -n-butyloxy1S-O-ethyl-deserpidate and the like, lower alkyl 18- O-lower alkyl-12-methoxy-deserpidates, e.g. methyl 12- methoxy-IS-O-methyI-deserpidate, ethyl 12-methoxy-18- O-methyl-deserpidate and the like, or therapeutically acceptable acid addition salts thereof.

An additional preferred group of compounds are the lower alkyl 18-O-lower alkyl-deserpidates, in which lower alkyl contains preferably from one to seven carbon atoms, and is represented by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, therapeutically acceptable acid addition salts, N-oxides or therapeutically acceptable acid addition salts of N-oxides thereof. Specific mem bers of this group are, for example, methyl l8-O-methyldeserpidate, methyl l8-O-ethyl-deserpidate, methyl 18-0- n-propyl-deserpidate, methyl 18-O-isopropyl-deserpidate, methyl 1B-O-n-butyI-deserpidate, methyl 18-O-secondary butyl-deserpidate, ethyl IS-O-methyl-deserpidate, ethyl 18-O-ethyl-deserpidate, ethyl 18 O-n-propyl-deserpidate, n-propyl IS-O-methyl-deserpidate, n-propyl l8-O-ethyldeserpidate, isopropyl 18-O-methyl-deserpidate, isopropyl 18 O-n-butyl-deserpidate, n-butyl 18 O-methyl-deserpidate, secondary butyl l8-O-methyl-deserpidate, n-pentyl 18-O-methyl-deserpidate and the like, or therapeutically acceptable acid addition salts thereof.

Other compounds having the useful pharmacological properties previously mentioned, are, for example, lower alkyl 18-O-lower alkyl-5-methyl-reserpates, e.g. methyl 5- methyl-IS-O-methyl-reserpate, methyl 18-O-ethyl-5-methyl reserpate, ethyl 5 methyl-l8-O-methyl-reserpate and the like, lower alkyl 18-O-lower alkyl-6-methyl-reserpates, e.g. methyl 6-methyl-18-O-methyl-reserpate, methyl l8- O-n-butyl-6-methyl-reserpate, ethyl 6-methyl-18-O-methylreserpate and the like, lower alkyl 18-O-lower alklyl-6- methyl-deserpidates, e.g. methyl 6-methyl-l8-O-methyldeserpidate, methyl 6-methyl-18 O-n-propyl-deserpidate, ethyl 6-methyl- 18 O-methyl-deserpidate and the like, lower alkyl l8-O-lower alkyl-9-methyl-deserpidates, e.g. methyl 9 methyl 18 O-methyl-deserpidate, methyl 9- methyl-18-O-ethyl-deserpidate, n-propyl 9-methyl-18 O- methyl-deserpidate and the like, lower alkyl l8-O-lower alkyl-1l-methyl-deserpidates, e.g. methyl ll-methyl-lS-O- methyl-deserpidate, ethyl l l-methyl-18-O-rnethyl-deserpidate, ethyl ll-methyl-lS-O-n-butyl-deserpidate and the like, lower alkyl l8-O-lower alkyl-10-methoxy-reserpates,

e.g. methyl 10-methoxy 18 O-methyl-reserpate, methyl 1S-O-ethyl-IO-methoxy-reserpate, ethyl 10-methoxy-l8-O- n-propyl-reserpate and the like, lower alkyl 9,10-dimethoxy-18-O-lower alkyl-reserpates, e.g. methyl 9,10-din1ethoxy-lS-O-methyl-reserpate, methyl 9,10-dimethoxy-l8-O- ethyl-reserpate, ethyl 9,lO-dimethoxy-18-O-methyl-reserpate, and the like, lower alkyl 18-O-lower alkyl-10,11- methylenedioxy-deserpidates, e.g. methyl 18-O-methyl-10, ll-methylenedioxy-deserpidate, ethyl 18-O-methyl-10,11- methylenedioXy-deserpidate and the like, lower alkyl 10- benzyloxy-lS-O-lower alkyl-deserpidates, e.g. methyl l0- benzyloxy-l8-O-methyl-deserpidate, methyl lO-benzyloxy- IS-O-ethyI-deserpidate, ethyl 10-benzyloxy-lS-O-methyldeserpidate and the like, lower alkyl ll-benzyloxy-lS-O- lower alkyl-deserpidates, e.g. methyl ll-benzyloxy-lS-O- methyl-deserpidate, methyl 11-benzyloxy-18 O-ethyl-de serpidate, ethyl ll-benzyloxy 18 O-methyl-deserpidate and the like, lower alkyl 18-O-lower alkyl-ll-methylmercapto-deserpidates, e.g. methyl 18-O-methyl-11-methylmercapto-deserpidate, methyl 18-O-ethyl-11 methylmercapto-deserpidate, ethyl 18-O-methyl-1l-methylmercaptodeserpidate and the like, lower alkyl 11-ethyl-mercapto 18-O-lower-alkyl-deserpidates, e.g. methyl ll-ethylmercapto-l8-O-methyl-deserpidate, ethyl 18-O-ethyl-11-ethylmercapto-deserpidate, n-propyl ll-ethylmercapto- 18-0- methyl-deserpidate and the like, lower alkyl 11-fluoro-18- O-lower alkyl-deserpidates, e.g. methyl ll-fluoro-lS-O- methyl-deserpidate, methyl 1l-fluoro-lS-O-ethyl-deserpidate, ethyl ll-fluoro- 18 -O-methyl-deserpidate and the like, lower alkyl 10-chloro-18-O-lower alkyl-deserpidates, e.g. methyl IO-chloro-l8-O-methyl-deserpidate, methyl 10- chloro-lS-O-ethyl-deserpidate, ethyl IO-chloro 18 O-nbutyl-deserpidate and the like, lower alkyl 10-brorno-18- O-lower alkyl-reserpates, e.g. methyl 10-bromo-l8-O- methyl-reserpate, methyl IO-bromo-lS-O-ethyl-reserpate, ethyl 10-bromo-lS-O-ethyl-reserpate and the like, lower alkyl -l7a-desmethoxy-17a-ethoxy-18-O-lower alkyl-reserpates, e.g. methyl 17oc-desmethoxy 17oz-6tl1OXY 18 O- methyl-reserpate, methyl l7a-desmethoxy-l7u-ethoxy-18- O-ethyl-reserpate and the like, lower alkyl l7u-desmethoxy 18 O-lower a1kyl-17a-n-propyloxy reserpates, e.g. methyl 17a-desmethoxy-18-O-methyl-17a-n-propyloxy-reserpate, ethyl 17u-desmethoxy-18-O-methyl-17a-n-propyloxy-reserpate and the like, lower alkyl l7oc-desmethoxyl7a-isopropyloxyl8-O-lower alkyl-reserpates, e.g. methyl 17a-desmethoxy-l7oc-isopropyloxy-18-O-methyl-reserpate, methyl l7zx-desmethoxy-lS-O-ethyl l7m-isopropyloXy-reserpate and the like, lower alkyl 17OL-d6S1'I16thOXY-17OC- ethoxy-l8-O-lower alkyl-deserpidates, e.g. methyl 171xdesmethoxy-17a-ethoxy-lS-O-methyl-deserpidate, methyl 17a-desmethoxy-17oc-ethoxy-l8-O-ethyl-deserpidate, ethyl 17u-desmeth0xy-17a-ethoxy 18 O-ethyl-deserpidate and the like, lower alkyl l7a-cyano-l7a-desmethoxy-l8-O- lower' alkyl-reserpates, e.g. methyl L-Cy3l'10-170c-d6S- methoxy-l8-O-methyl-reserpate, methyl 17 a-cyano 170cdesmethoxy-lS-O-ethyl-reserpate and the like, lower alkyl l7oc-cyano-l7a-desmethoxy-18-O-lower alkyl-deserpidates, e.g. methyl l7oc-cyano-l7u-desmethoxy-lS-O-methyl-deserpidates and the like, or analogous compounds, and the therapeutically acceptable acid addition salts thereof.

Also mentioned as preferred groups of compounds within the scope of the invention are, for example, lower alkoxy-lower alkyl 18-O-lower alkyl-reserpates and lower alkoxy-lower alkyl 18-O-lower alkyl-deserpidates, or the therapeutically acceptable acid addition salts thereof. Lower alkyl of the lower alkoxy-lower alkyl portion represents a lower alkylene radical containing from two to three carbon atoms, which separates the lower alkoxy group from the carbon atom of the carboxyl group by the same number of carbon atoms, and lower alkoxy has from one to four carbon atoms, and the lower alkyl group attached to the oxygen atom of the l8-position contains preferably from one to four carbon atoms. The lower alkoxy-lower alkyl portion stands, for example, for Z-methoxyethyl, 2-ethoxyethyl, Z-methoxypropyl, 3- rnethoxypropyl and the like, and lower alkyl may stand for methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like. Specific compounds of this group are, for example, Z-methoxyethyl 18-O-methyl-reserpate, 2- methoxyethyl 18-O-ethyl-reserpate, Z-ethoxyethyl 18-O- methyl-reserpate, 2-ethoxyethyl IS-O-n-propyl-reserpate,

,Z-methoxypropyl 18-O-methyl-reserpate, 3-methoxyprovpyl IS-O-methyl-reserpate, Z-methoxyethyl 18-O-methyl deserpidate, 2 methoxyethyl 18 O-ethyl-deserpidate, 2- ethoxyethyl l8-O-methyl-deserpidate and the like, or therapeutically acceptable acid addition salts thereof.

An additional group of preferred compounds is represented by the N,N-di-lower alkyl-amino-lower alkyl 18- O-lower alkyl-reserpates and N,N-di-lower alkyl-aminolower alkyl 18-O-lower alkyl-de-serpidates, and the therapeutically acceptable acid addition salts thereof. N,N-dilower alkyl-amino may stand for N,N-dimethylamino, N- ethyl-N-rnethylamino, N,N-diethylamino and the like, and lower alkyl, to which N,N-di-lower alkyl-amino is attached, stands for :a lower alkylene radical containing from two to three carbon atoms, which separates N,N-dilower alkyl-amino from the carbon atom of the carboxyl group by from two to three carbon atoms. The N,N-dilower alkyl amino-portion stands, for example, for 2-N,

N-dimethylaminoethyl, 2-N,N-diethylaminoethyl, 2-N,N- dimethylaminopropyl, 3-N,N-dimethylaminopropyl and the like. Specific compounds of this group are, for example, 2-N,N-dimethylaminoethyl l8-O-methyl-reserpate, 2-N,N-dimethylaminoethyl 18 O-ethyl-reserpate, 2N,N- diethylaminoethyl l8-O-methyl-reserpate, 3-N,N-dimethylaminopropyl IB-O-methyl-reserpate, 2-N,N-dimethylaminoethyl IS-O-methyI-deserpidate, 2-N,N-dimethylaminoethyl IS-O-ethyl-deserpidate, 2-N,N-dimethylaminopropyl IS-O-methyLdeserpidate and the like, or therapeutically acceptable acid addition salts thereof.

Another group of preferred compounds having the above-given properties is represented by the formula:

aw H

in which each of the groups R and R represents lower alkyl, containing preferably from one to seven carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, n-pentyl, isopentyl, n-hexyl, nheptyl and the like, and R represents lower alkoxy containing from one to four carbon atoms, particularly methoxy, as well as ethoXy, n-propyloxy, isopropyloxy, nbutyloxy and the like, whereby R is preferably attached to the l-position or the ll-position, therapeutically acceptable acid addition salts, N-oxides or therapeutically acceptable acid addition salts of such N-oxides thereof.

These compounds are represented by the lower alkyl l8-epi-O-lower alkyl-reserpates, in which lower alkyl contains from one to four carbon atoms, and represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, therapeutically acceptable acid addition salts, N- oxides or therapeutically acceptable acid addition salts of such N-oxides thereof. These compounds having pronounced sedative and tranquilizing effect with a fast onset and an easily controllable duration of action, accompanied by negligible antihypertensive properties, as well as strong anti-fibrillatory activities, may be represented, for example, by methyl 18-epi-O-methyl-reserpate, methly lS-epi-O-ethyl-reserpate, methyl IS-epi-O-n-propyl-reserpate, methyl l8-epi-O-isopropyl-reserpate, methyl l8- epi-O-n-butyl-reserpate, methyl 18-epi-O-isobutyl-reserpate, methyl 18-epi-O-n-pentyl-reserpate, ethyl l8-epi-O- n-hexyl-reserpate, ethyl 18-epi-O-methyl-reserpate, ethyl 1S-epi-O-ethyl-reserpate, ethyl IS-epi-O-n-propyl-reserpate, ethyl 18-epi-om-butyl-reserpate, n-propyl 18-epi-O- methyl-reserpate, n-propyl l8-epi-O-ethyl-reserpate, isopropyl IS-epi-O-methyl reserpate, isopropyl l8-epi-O-npropyl-reserpate, n-butyl 18-epi-O-methyl-reserpate, nbutyl 18-epi-O-etl1yl-reserpate, isobutyl l8-epi-O-methylreserpate, n-pentyl 18-epi-O-methyl-reserpate, n-heXyl 18- epi-O-methyl-reserpate and the like, or therapeutically acceptable acid addition salts, such as the hydrochlorides and the like, of these compounds.

Other compounds of the aforementioned formula are, for example, lower alkyl lfi-epi-O-lower alkyl-9-methoxy-deserpidates, e.g. methyl 9-methoxy-l8-epi-Omethyldeserpidate, methyl 18-epi-O-ethyl-9-methoxy-deserpidate, methyl 9-methoxy-l8-epi-O-n-propyl-deserpidate, ethyl 9- methoXy-l8-epi-O-methyl-deserpidate and the like, lower alkyl lfl-epi-O-lower alkyl-IO-methoxy-deserpidates, e.g. methyl lO-methoxy-lS-epi-O-methyl-deserpidate, methyl lS-cpi-O-ethyldO-methoxy-deserpiclate, methyl l0-meth oXy-l8-epi-O-n-propyldeserpidate, ethyl l0-methoXy-l8- epi-O-methyl-cleserpidate, n-propyl l0- methoXy-l8-epi- O-methyl-deserpidate, isopropyl IO-methoxy-lE-epi-O- methyl-deserpidate and the like, lower alkyl ll-ethoxyl8-epi-O-lower alkyl-deserpidates, e.g. methyl ll-ethoxyl8-epi-O-methyl-deserpidate, methyl 1lethoxy-l8-epi-O- ethyl-deserpidate and the like, lower alkyl 18-epi-O-lower alkyl-l1-n-propyloxy-deserpidates, e.g. methyl l8-epi-O- methyl-1l-n-propyloXy-deserpidate, methyl 18-cpi-O-ethyl-l1-n-propyloxy-deserpidate and the like, lower alkyl 11- isopropyloxy-l8-epi-O-lower alkyl-deserpidates, e.g. methyl 1l-isopropyloXy-l8-epi-O-methyl-deserpidate, ethyl llisopropyloxyd8-epi-O-methyl-deserpidate and the like, lower alkyl ll-n-butyloxy-l8-epi-O-lower alkyl-deserpidates, e.g. methyl 1l-n-butyloxy-l8-epi-O-methyl-deserpidate, methyl 11-n-butyloxy-1S-epi-O-ethyl-deserpidate and the like, lower alkyl 18-epi-O-lower alkyl-l2-methoxydeserpidates, e.g. methyl 12-methoxy-lS-epi-O-methyl-deserpidate, ethyl 12-methoxy-l8-epi-O-methyl-deserpidate and the like, or therapeutically acceptable acid addition salts thereof.

An additional preferred group of compounds are the lower alkyl l8-epi-O-lower alkyl-deserpidates, in which lower alkyl contains preferably from one to seven carbon atoms, and is represented by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, therapeutically acceptable acid addition salts, N-oxides and therapeutically acceptable acid addition salts of N-oxides thereof. Specific members of this group are, for example, methyl 18- epi-O-methyl-deserpidate, methyl 18-epi-O-ethyl-deserpidate, methyl 18-epi-O-n-propyl-deserpidate, methyl 18- epi-O-isopropyl-deserpidate, methyl l8-epi-O-n-butyl-deserpidate, methyl 18-epi-O-secondary butyl-deserpidate, ethyl l8-epi-O-methyl-deserpidate, ethyl l8-epi-O-ethyldeserpidate, ethyl 1S-epi-O-n-propyl-deserpidate, n-propyl 18-epi-O-methyl-deserpidate, n-propyl 18-epi-O-ethyl-deserpidate, isopropyl 18epi-O-methyl-deserpidate, isopropyl 1S-epi-O-n-butyl-deserpidate, n-butyl IS-epi-O-methyl-deserpidate, secondary butyl IS-epi-O-methyl-deserpidate, n-pentyl 18-epi-O-methyl-deserpidate and the like, or therapeutically acceptable acid addition salts thereof.

Other compounds having the useful pharmacological properties previously mentioned, are, for example,

lower alkyl l8-epi-O-lower alkyl-S-methyl-reserpates,

e.g. methyl S-methyl-l S-epi-O-methyl-reserpate,

methyl l8-epi-O-ethyl-5-methyl-reserpate,

ethyl S-methyl-lS-epi-O-methyl-reserpate and the like,

lower alkyl 18-epi-O-lower alkyl-6-methyl-reserpates,

e.g. methyl 6-methyl-18-epi-O-methyl-reserpate,

methyl l8-epi-O-n-butyl-6-methyl-reserpate,

ethyl 6-methyl-l8-epi-O-methyl-reserpate and the like,

lower alkyl lS-epi-O-lower alkyl-6-methyl-deserpidates,

e.g. methyl 6-methyl-18-epi-O-methyl-deserpidate,

methyl 6-methyl-l 8-epi-O-n-propyl-deserpidate,

ethyl 6-methyl-l8-epi-O-methyl-deserpidate and the like,

lower alkyl 18-epi-O-lower alkyl-9-methyl-deserpidates,

e.g. methyl 9-methyl-18-epi-Omethyl-deserpidate,

methyl 9-methyl-l S-epi-O-ethyl-deserpidate,

n-propyl 9-methyl-1S-epi-O-methyl-deserpidate and the like,

lower alkyl IS-epi-O-lower alkyl-1l-methyl-deserpidates,

e.g. methyl ll-methyl-l8-epi-O-methyl-deserpidate,

ethyl ll-methyl-l8-epi-O-methyl-deserpidate,

ethyl 1l-methyl-l8-epi-O-n-butyl-deserpidate and the like,

lower alkyl l8epi-O-lower alkyl-lO-methoxy-reserpates,

e.g. methyl lO-methoxy-l8-epi-O-methyl-reserpate,

methyl lS-epi-O-ethyl-ltl-methoxy-reserpate,

ethyl lO-methoxy-lS-epi-O-n-propyl-reserpate and the like,

lower alkyl 9,lO-dimethoxy-lS-epi-O-lower alkyl-reserpates,

e.g.methyl 9, IO-dimethoxy-l 8epi-O-methyl-reserpate,

methyl 9, l O-d imethoXy-l 8-epi-O-ethyl-reserpate,

ethyl 9,lO-dimethoxy-lS-epi-O-methyl-reserpatc and the like,

lower alkyl 'l8-epi-O-lower alkyl-10,1l-methylenedioxydeserpidates,

r e.g. methyl l8-epi-O-methyl-l0,l l-methylenedioxydeserpidate,

ethyl 18-epi-O-methyl-10, l l-methyleneclioxy-deserpidate and the like,

lower alkyl IO-benzyloxy-l8-epi-O-lower alkyl-deserpidates,

e.g. methyl IO-benzyloxy-18-epi-O-methyl-deserpidate,

methyl 10-benzyloxy-lS-epi-O-ethyl-deserpidate,

ethyl lO-benzyloxy-l8-epi-O-methyl-deserpidate and the like,

lower alkyl ll-benzyloxy-lS-epi-O-lower alkyl-deserpidates,

e.g. methyl 1l-benzyloxy-l8-epi-O-methyl-deserpidate,

methyl 1l-benzyloxy-18-epi-O-ethyl-deserpidate,

ethyl 1l-benzyloxy-l8-epi-O-methyl-deserpidate and the like,

lower alkyl l8-epi-O-lower alkyl-1 l-methylmercaptodeserpidates,

e.g. methyl l8-epi-O-methyl-1l-methylmercapto-deserpidate,

methyl IS-epi-O-ethyl-l l-methylmercapto-deserpidate,

ethyl l8-epi-O-methyl-l 1-methylmercapto-deserpidate and the like,

lower alkyl 1l-ethylmercapto-lS-epi-O-lower alkyldeserpidates,

e.g. methyl 11-ethylmercapto-18-epi-O-rnethyl-deserpidate,

ethyl IS-epi-O-ethyl-ll-ethylmercapto-deserpidate,

n-propyl l l-ethylmercapto-l 8-epi-O-methyl-deserpidate and the like,

lower alkyl ll-fluoro-l8-epi-O-lower alkyl-deserpidates,

e.g. methyl 1l-fiuoro-l8-epi-O-methyl-deserpidate,

methyl 1l-fiuoro-l8-epi-O-ethyl-deserpidate,

ethyl 1l-fluoro-l8-epi-O-methyl-deserpidate and the like,

lower alkyl 10-chloro-l8-epi-0-lower alkyl deserpidates,

e.g. methyl 10chlor0-18-epi-O-methyl-deserpidate,

methyl IO-chloro-l8-epi-O-ethyl-deserpidate,

ethyl 10-chloro-l8-epi-O-n-butyl-deserpidate and the like,

lower alkyl IO-bromo-lS-epi-O-lower alkyl-reserpates,

e.g. methyl 10-bromo-lS-epi-O-methyl-reserpate,

methyl l-bromo-1S-epi-O-ethyl-reserpate,

ethyl IO-bromo-l8-..pi-O-ethyl-reserpate and the like,

lower alkyl 17u-desmethoxy-l7a-ethoxy-1 8-epi-O-lo-wer alkyl-reserpates,

e.g. methyl l7a-desmethoxy-l7a-ethoxy-18-epi-O- methyl-reserpate,

methyl l7a-desmethoxy-l7a-ethoxy-1S-epi-O-ethyl-reserpate and the like,

lower alkyl 17a-desmethoxy-lS-epi-O-lower alkyl-17ampropyloxy-reserpates,

e. g. methyl l7oc-desmethoxy-l 8-epi-O-methyll 7a-npropyloxy-reserpate,

ethyl l7a-desmethoxy-lS-epi-O-methyl-l7u-n-propyloxyreserpate and the like,

lower alkyl 17a-desrnethoxy-17x-isopropyloxy-18-epi-O- lower alkyl-reserpates,

e.g. methyl l7et-desmethoxy-l7a-isopropyloxy-18-epi-O- methyl-reserpate,

methyl l7tx-desmethoxy-lS-epi-O-ethyl-l7a-isopropyloxyreserpate and the like,

lower alkyl l7oc-desmethoxy-17ot-ethoxy-l8-epi-O-lower alkyl-deserpidates,

e.g. methyl l7u-desmethoxy-llot-ethoxy-1 -epi-O-methyldeserpidate,

methyl 17u-desmethoxy-17a-ethoxy-1S-epi-O-ethyldeserpidate,

ethyl l7 ot-desmethoxy flwethoxy- 1 S-epi-O-ethyldeserpidate and the like,

lower alkyl 17wcyano l'lwdesmethoxy-lS-epi-O-lower alkyl-reserpates,

e.g. methyl 17a cyano-l7ot-desmethoxy-lS-epi-O-methylreserpate,

methyl l7oz-cyano-17a-desmethoxy-1S-epi-O-ethylreserpate and the like,

lower alkyl 17a-cyano-l7a-desmethoxy-l8-epi-O-lower alkyl-deserpidates,

1% e. g. 17a-cyano-17a-desmethoxy-1 8-epi-O-methyldeserpidate, methyl l7a-cyano-l7a-desmethoxy-l8-epi-O-ethyl deserpidate and the like, or analogous compounds, and therapeutically acceptable acid addition salts thereof.

Also mentioned as preferred compounds within the scope of the invention are, for example, lower alkoxylower alkyl l8-epi-O-lower alkyl-reserpates and lower alkoxy-lower alkyl l8-epi-O-lower alkyl-deserpidates, or therapeutically acceptable acid addition salts thereof. Lower alkyl in the lower alkoxy-lower alkyl portion represents lower alkylene containing from two to three carbon atoms, which separates the lower alkoxy group from the carbon atom of the carboxyl group by the same number of carbon atoms, and lower alkoxy has from one to four carbon atoms, and the lower alkyl group attached to the oxygen atom of the 18-position contains preferably from one to four carbon atoms. The lower alkoxy-lower alkyl portion represents, for example, 2-methoxyethyl, 2-ethoxyethyl, Z-methoxypropyl, 3-methoxyethyl and the like, and lower alkyl may stand for methyl, ethyl, n-

propyl, isopropyl, n-butyl, isobutyl and the like. Specific compounds of this group are, for example,

2-methoxyethyl l8-epi-O methyl-reserpate, 2-methoxyethyl 18-epi-O-ethyl-reserpate,

Z-ethoxyethyl l8-epi-O-methyl-reserpate,

Z-ethoxyethyl 18-epi-n-propyl-reserpate, Z-methoxypropyl 18-epi-O-methyl-reserpate, 3-methoxypropyl 18-epi-O-methyl-reserpate, Z-methoxyethyl l8-epi-O-methyl-deserpidate, Z-methoxyethyl l8-epi-O-ethyl-deserpidate,

Z-ethoxyethyl l8-epi-O-methyl-deserpidate and the like, or therapeutically acceptable acid addition salts thereof.

An additional group of compounds is represented by the N,N-di-lower alkyl-amino-lower alkyl 18-epi-0-lower alkyl-reserpates and N,N di lower alkyl-amino-lower alkyl l8-epi-O-lower alkyl-deserpidates, and therapeutically acceptable acid addition salts thereof. N,N-dilower alkyl-amino represents, for example, N,N-dimethylamino, N-ethyl-N-methylamino, N,N-diethylamino and the like, and lower alkyl, to which N,N-dilower alkylamino is attached, represents lower alkylene containing from two to three carbon atoms, which separates N,N- di-lower alkyl-amino from the carbon atom of the carboxyl group by from two to three carbon atoms. The N,N-di-lower alkyl amino-lower alkyl portion represents, for example, 2-N,N-dimethylaminoethyl, 2-N,N-diethylaminoethyl, 2-N,N-dimethylaminopropyl, 3-N,N-dimethylaminopropyl and the like. Specific compounds of this group are, for example, 2-N,N-dimethylarninoethyl l8-epi-O-methyl-reserpate, 2-N,N-dimethylaminoethyl lS-epi-O-ethyl-reserpate, 2-N,N-diethylaminoethyl lS-epi-O-methyl-reserpate, 3-N,N-dimethylaminopropyl lS-epi-O-methyl-reserpate, 2-N,N-dimethylaminoethyl 18-epi-O-methyl-deserpidate, 2-N,N-dimethylaminoethyl l8-epi-O-ethyl-deserpidate, 2-N,N-dimethylaminopropyl 18-epi-O-methyl-deserpidate and the like or therapeutically acceptable acid addition salts thereof.

The compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new compounds or derivatives thereof, such as therapeutically acceptable acid addition salts, N-oxides or therapeutically acceptable acid addition salts of N-oxides thereof, in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed inert substances, which are compatible with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known inert carrier used in medicaments. The pharmaceutical preparation may be in solid form, for example, as tablets, capsules, dragees and the like, or in liquid form, for example, as solutions, suspension, emulsions and the like. If desired, they may contain additional substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers or any other auxiliary substances. They may also contain, in combination, other therapeutically useful substances.

Compounds of this invention can be formed by etherifying in an 18-hydroxy-3-epi-allo-yohimbane l6-carboxylic acid ester, particularly in a compound having one of the following formulae:

in which R R R R R and R have the previously given meaning, a salt, an N-oxide or a salt of an N-oxide thereof, the free hydroxyl group attached to the 18-position by treatment with a diazo-compound in the presence of a strong inorganic Lewis acid, and, if desired, converting a resulting salt into the free base, and/or, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof, and/ or, if desired, converting a resulting mixture of isomers into the single isomers.

A salt of the starting material or of an N-oxide thereof, is an addition salt with an acid, primarily a salt with an inorganic, such as a mineral, acid, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acid and the like. An acid addition salt may also be a salt with the strong in organic Lewis acid catalyzing the etherification reaction, e.g. fluoboric acid and the like; such salt may be formed during the reaction.

The starting material, a salt, an N-oxide or a salt of an N-oxide thereof is reacted with a diazo compound of the formula R N in which R has the previously given meaning, particularly with an aliphatic diazo-hydrocarbon, for example, a lower diazo-alkane, e.g. diazomethane, diazoethane, n-diazopropane, diazoisopropane, n-diazobutane, diazoisobutane, n-diazopentane and the like, as well as with a substituted aliphatic diazo-hydrocarbon, such as an etherified hydroxy-lower diazo-alkane, particularly a lower aikoxy-lower diazo-alkane, a tertiary amino-lower diazo-alkane, particularly an N,N-di-lower alkylamino-lower diazo-alkane and the like, or any other suitable diazo reagent, in the presence of a strong inorganic Lewis acid. Fluoboric acid, which may be employed in the form of a concentrated aqueous solution (for example, as an about 12 N to an about 16 N aqueous solution), represents the preferred reagent. Other Lewis acid reagen s may be, for example, perchloric acid (preferably in anhydrous form) and the like. Due to the salt-forming properties of free starting material, the Lewis acid, catalyzing the etherification of the 18-hydroxyl group, is used in excess of one mol, whenever the free base is present; an about one to an about two hundred, preferably an about ten to an about fifty, percent excess appears to be sufficient to promote the etherification reaction.

The reaction is carried out in the presence of an organic solvent, which is inert towards the starting material, the diazo reagent and the Lewis acid. Appropriate diluents are, for example, halogenated lower aliphatic hydrocarbons, e.g. methylene chloride, chloroform, ethylene chloride, trichloroethane, tetrachloroethane and the like, ethers, e.g. diethyl ether, tetrahydrofuran and the like, lower alkyl lower alkanoates, e.g. methyl acetate, ethyl acetate and the like, acetonitrile or any other useful solvent, as well as mixtures of solvents, such as those mentioned hereinabove. A solution of the diazo reagent in an inert solvent, such as an ether, e.g. diethyl ether and the like, or a halogenated hydrocarbon, e.g. methylene chloride and the like, or a mixture of solvents, may be added to the mixture of the starting material and the Lewis acid, preferably kept in solution. The diazo compound may also be distilled out of a solution into the solution of the mixture of the starting material and the Lewis acid. Furthermore, the latter mixture may also be given to a solution of the diazo reagent.

The reaction may be carried out at room temperature; however, cooling of the reaction mixture to below room temperature, for example, to from about 10 to about -20, especially to from about 0 to about 15, may be advantageous. If necessary, the reaction may be carried out in the atmosphere of an inert gas, e.g. nitrogen and the like.

An excess of the diazo reagent present at the end of the reaction may be destroyed, for example, by adding an acid, preferably an easily esterifiable organic carboxylic acid, e.g. acetic, benzoic acid and the like.

The desired product may be isolated and separated from any by-products according to standard procedures, e.g. extraction, adsorption and elution, crystallization, etc. and purified, for example, by recrystallization, if necessary, after treatment of a solution thereof with an adsorbent, e.g. aluminum oxide, charcoal, diatomaceous earth and the like.

The above-described procedure may be illustrated by the treatment of a lower alkyl reserpate or a lower alkyl 18-epi-reserpate with a lower diazo-alkane in the presence of a strong Lewis acid, such as fluoboric acid and the like, to form the desired lower alkyl 18-0lower alkylreserpate and lower alkyl l8-epi-O-lower alkyl-reserpate, respectively, which, if desired, may be converted into an acid addition salt, particularly a mineral acid, e.g. hydrochloric acid and the like, addition salt thereof. For example, upon treatment of methyl reserpate or methyl 18- epi-reserpate with diazomethane, diazoethane and the like, in the presence of fluoboric acid the methyl 18-O-methylreserpate, methyl IS-O-ethyl-reserpate and the like, and methyl 1S-epi-O-methyl-reserpate, methyl 18-epi-O-ethylreserpate, and the like, respectively, may be prepared.

The starting materials used in the above procedure may be obtained, for example, by reacting an 18-organic sulfonyloxy-3-epi-allo-yohimbane 16-carboxylic acid ester, particularly .a compound having one of the formulae:

in which R R R R R and R have the previously given meaning, and R represents an organic radical, particularly monocyclic carbocyclic aryl, such as phenyl, or primarily substituted phenyl, a salt, an N-oxide or a salt of an N-oxide thereof, with Water to form the desired 18- hydnoxy-3-epfi-allo-yohimbane l6-carboxylic acid ester, such as the compound of the previously given formula, and, if desired, converting a resulting compound into a salt, an N-oxide or a salt of an N-oxide thereof.

Substituted phenyl groups representing R contain preferably electron-withdrawing substituents, particularly halogeno, such as bromo, as well as chloro, iodo and the like; nitro or any other suitable electron-withdrawing group, as well as methyl and the like, may also serve as substituents. These substituents may be attached to the 2- position, or more especially to the 3- or the 4-position, as well as in two or more than two of these positions simultaneously. R in the above formulae stands, therefore, primarily for halogenophenyl, particularly bromo-phe-nyl and the like, nitro-phenyl, as well as phenyl and the like. It may also stand for another organic radical, such as an aliphatic radical, for example, lower alkyl, e.g. methyl, ethyl and the like.

Hydrolysis of the organic sulfonyloxy group in the resulting l8-organic sulfonyloxy-3-epi-allo-yohimbane l6- carboxylic acid ester, may be carried out by treatment with Water, preferably in the presence of an amine, especially a tertiary amine, such as, for example, an N,N,N- tri-lower alkyl-amine, e.g. N,N,N-trimethylamine, N- ethyl-N,N-dimethylamine, N,N,N-t-riethylamine and the like, as Well as an N,N,N,N'-tetra-lower al kylalkylenediamine, e.g. N,N,N,N-tetramethyl-l,6-hexylenediamine and the like, a l-lower alkyl-N,N-alkylene-imine, e.g. 1- methyl-pyrrolidine, l-methyl-piperidine, l-ethyl-piperidine and the like, a 4-loWer alkyl-morpholine, e.g. 4- methyl-morpholine, 4-ethyl-morpholine and the like, monocyclic azacyclic aryl compounds, such as pyridine, collidine and the like, or any other suitable reagent. Preferably, hydrolysis is achieved by heating the mixture to an elevated temperature, if necessary, under pressure or in the atmosphere of an inert gas, eg. nitrogen. The hydrolysis reaction proceeds with inversion, i.e. an 18aorganic sulfonyloxy-3-epi-allo-yohimbane l6-carboxylic acid ester yields upon hydrolysis according to the above procedure an 18f3-hydroxy-3-epi-allo-yohirnbane l6-carboxylic acid ester, or an 18(3-organic sulfonyloxy-B-epiallo-yohimbane 16-carboxylic acid ester yields an 18cchydroxy-3-epi-allo-yohimbane l6-carboxylic acid ester, respectively.

The above l8-organic sulfonyloxy-3-epi-allo-yohimbane 16-carboxylic acid esters are known or may be prepared according to known methods, for example, by esterification of the l8-hydroxy-3-epi-allo-yohimbane 16-carboxylic acid esters with an organic sulfonyl halide, particularly a monocyclic aryl sulfonyl halide, such as benzene sulfonyl chloride, or particularly benzene sulfonyl chloride, in which the benzene ring is substituted with an electron-withdrawing substituent, such as halogeno, such as bromo, or chloro, iodo and the like, nitro, or any other suitable substituent, such as methyl and the like, in the presence of a base, particularly an organic tertiary base, e.g. pyridine, collidine and the like. In the esterification step, the base, such as, for example, pyridine and the like 18 may also serve as the diluent; other suitable, inert solvents may be added, if necessary. The reaction is carried out under cooling or at room temperature, preferably under the exclusion of moisture.

In view of the fact that during the hydrolysis of 18- organic sulfonyloxy-3-epi-allo-yohimbane l6-carboxylic acid esters according tothe above procedure epimerization occurs at the carbon atom representing the l8-position, the 18-hydroxy-3-epi-allo-yohimbane 16-carbo-xylic acid ester used as the starting material for the preparation of the corresponding l8-carbocyclic aryl-sulfonyloxy compounds and the l8-hydroxy-3-epi-allo-yohimbane 16- carboxylic acid esters obtained from the hydrolysis of the I latter, have different configurations for the 18 hydroxyl group. For example, upon esterification of methyl reserpate to the methyl 18-O-(4-brorno-phenyl-sulfonyl)-reserpa-te and hydrolysis of the latter with water, preferably in the presence of N,N,N-triethylami ne and the like, the methyl 18-epi-reserpate is formed. The procedure is particularly suited for the manufacture of 18a-hydroxy-3-epiallo-yohimbane 16-carboxylic acid esters, which can thus be derived from l8fi-hydroxy-3-epi-allo-yohimbane l6- carboxylic acid esters having the configuration present in naturally occurring starting materials or in compounds prepared according to known totally synthetic procedures.

The starting materials may also be prepared, for example, by alcoholysis of an IS-esterified hydroxy-3-epiallo-yohimbane 16-carb0xylic acid ester, particularly of a compound having one of the formulae:

N RA H in which R R R R R and R have the previously given meaning, and Ac stands for the acyl radical of an organic carboxylic acid, a salt, an N-oxide or a salt of an N-oxide thereof. Alcoholysis is carried out by treatment with an alcohol, such as an alcohol of the formula R OH, in which R has the previously given meaning, in the presence of an alcoholysis reagent, such as an alkali metal, e.g. sodium, potassium and the like, compound of the alcohol used in the alcoholysis or any other suitable alcoholysis catalyst; the reaction is preferably completed at an elevated temperature.

The alcoholysis reaction is particularly suited for the preparation of 1S-hydroxy-3-epi allo-yohimbane l6-carboxylic acid esters, which can be derived from naturally occuring esters of the above type, especially lower alkyl reserpates, e.g. methyl reserpate, ethyl reserpate, n-propyl reserpate and the like, as well as lower alkyl deserpidates, e.g. methyl deserpidate and the like.

18fl-hydroxyl-3-epi-allo-yohimbane 16-carboxylic acid esters may also be prepared, for example, by subjecting a (16 l8)-lactone of an 1Sfl-hydroxy-S-epi-allo-yohim- 19 bane l6B-carboxylic acid, such as a compound of the formula:

in which R R R R and R have the previously given meaning, a salt, an N-oxide or a salt of an N-oxide thereof, to alcoholysis with a lower alkanol or a substituted lower alkanol, such as an etherified hydroxy-lower alkan01, a tertiary amino-lower alkanol and the like, particularly an alcohol of the formula R -OH, in which R has the above-given meaning, in the presence of an alcoholysis catalyst. The alcoholysis reaction may be carried out, for example, by treating the lactone compound used as the starting material with a lower alkanol, or a substituted lower alkanol, such as a carbocyclic aryllower alkanol, an etherified hydroxy-lower alkanol, a tertiary amino-lower alkanol and the like, in the presence, for example, of an alkali metal, e.g. sodium, potassium and the like, compound of the alcohol used in the alcoholysis, or any other suitable alcoholysis catalyst, e.g. potassium cyanide, benzyl trimethyl ammonium hydroxide and the like. Although this reaction may proceed under cooling or at room temperature, the mixture is advantageously heated, if necessary, in the atmosphere of an inert gas, e.g. nitrogen.

The above alcoholysis reaction is particularly suited for the preparation of starting materials, which are easily accessible through known totally synthetic procedures.

The IS-etherified hydroxy-S-epi-allo-yohimbane 16-carboxylic acid esters, salts, N-oxides or salts of N-oxides thereof, may also be prepared, for example, by reacting an 18-organic sulfonyloxy-3-epi-allo-yohimbane 16-carboxylic acid ester, particularly a compound of one of the formulae:

and

in which R R R R R and R have the previously given meaning, and R stands for an organic radical, a salt, an N-oxide or a salt of an N-oxide thereof, with a hydroxylated compound, particularly a compound of the formula R -OH, in which R has the previously given meaning, and, if desired, carrying out the optional steps.

The group R in the above formula has the previously given meaning and is preferably a monocyclic carbocyclic aryl group, which may be represented by phenyl, or, more particularly, by substituted phenyl. The latter is preferably a phenyl radical substituted in the 2-position, 3- position and/ or the 4-position by an electron-withdrawing substituent, particularly halogeno, primarily bromo, as well as fiuoro, chloro or iodo, nitro, as well as carbolower alkoxy, e.g. carbomethoxy, carbethoxy and the like, carbamyl, cyano or any other suitable groups. Lower alkyl, especially methyl and the like, may also be a suitable substituent. The group R may, therefore, be represented by phenyl, or primarily by halogeno-phenyl, e.g. 4-bromo-phenyl and the like, nitro-phenyl, e.g. 3- nitro-phenyl, 4-nitro-phenyl and the like, cyano-phenyl, e.g. 4-cyano-phenyl, as well as di-substituted or tri-substituted phenyl radicals containing such groups. R may also stand for other organic radicals, such as an aliphatic radical, for example, lower alkyl, e.g. methyl, ethyl and the like.

Alcoholysis, particularly with a compound of the formula R -OH, such as with a lower alkanol, e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol and the like, a lower alkenol, e.g. 2-propenol and the like or any other suitable hydroxylated compound may be carried out in the absence, but more preferably in the presence of an alcoholysis reagent. Such reagent is represented by an amine, such as a tertiary amine, especially an aliphatic tertiary amine, such as an N,N,N-tri-l0wer alkyl-amine, e.g. N,N,N-trimethylamine, N-ethyl-N,N-dimethylamine, N,N,-diethyl-N-methylamine, N,N,N,-triethylamine and the like, an N,N,N',N'-tetra-lower alkyl-lower alkylenediamine, e.g. N,N,N,N'-tetramethyl-l,S-pentylene-diamine, N,N,N',N'-tetramethyl-l,6-hexylene-diamine, N,N, N,N tetraethyl-l,6-hexylenediamine, N,N,N',N-tetramethyl-1,7-heptylene-diamine and the like, a l-lower alkyl- N,N-alkylene-imine, in which alkylene contains from four to six carbon atoms, e.g. l-methyl-pyrrolidine, lmethyl-piperidine, l-ethyl-piperidine, 1-methyl-N,N-hexamethylene-imine and the like, 4-lower alkyl-morpholine, e.g. 4-methyl-morpholine, 4-ethyl-morpholine and the like, 1,4-di-lower alkyl-piperazine, e.g. 1,4-dimethyl-piperazine and the like, or any other suitable aliphatic tertiary amine, as well as heterocyclic compounds containing a tertiary nitrogen atom, e.g. pyridine, collidine and the like, or any other suitable organic amine.

The alcoholysis may be carried out using the hydroxylated compound, particularly the compound of the formula R -OH, for example, a lower alkanol, as the diluent; any other inert solvent, such as, for example, p dioxane and the like, may be added to ensure complete solution. The reaction is preferably completed at an elevated temperature, if necessary under an increased pressure, or in the atmosphere of an inert gas, such as nitrogen.

The above procedure may be illustrated by the reaction of a lower alkyl 18-O-(halogeno-phenyl)-sulfonyl-reserpate, such as methyl 18-O-(4-bromo-phenyl)-sulfonylreserpate and the like, or of a lower alkyl l8-O-(nitrophenyl)-sulfonyl-reserpate, e.g. methyl 18-O-(4-nitrophenyl)sulfonyl-reserpate, methyl 18-O-(3-nitro-phenyl)- sufonyl-reserpate and the like, with a lower alkanol, e.g. methanol, ethanol, n-propanol, isopropanol and the like, preferably in the presence of a tertiary amine, e.g. N,N,N- triethylamine, pyridine and the like, to form the desired lower alkyl l8-epi-O-lower alkyl-reserpate, e.g. methyl 18- epi-O-methyl-reserpate, methyl IS-epi-Oethyl-reserpate, methyl 18-epi-O n-propyl-reserpate, methyl l8-epi-O-isopropyl-reserpate and the like. Or, upon treatment of a lower alkyl 18-epi-O-(halogeno-phenyl)-sulfonyl-reserpate, e.g. methyl l8-epi-O-(4-bromo-phenyl)-reserpate and the like, or of a lower alkyl 18-epi-O-(nitro-phenyD- sulfonyl-reserpate, e.g. methyl 18-epi-O-(4-nitro-phenyl)- sulfonyl-reserpate, methyl 18-epi-O( 3-nitro-phenyl su1' fonyl-reserpate and the like, with a lower alkanol, e.g. methanol, ethanol, n-propanol, isopropanol and the like, preferably in the presence of a tertiary amine, e.g. N,N,N- triethylamine, pyridine and the like, the lower alkyl 18- O-lower alkyl-reserpates, e.g. methyl l8-O-methyl-resero-so -Ae in which R R R R R and R have the previously given meaning, and Ar represents halogeno-phenyl or nitro-phenyl, salts, N-oXides and salts of N-Oxides thereof, which compounds are intended to be included within the scope of this application. These compounds are preferred intermediates used in the conversion of compounds with the 18,8-oonfiguration into those having the 180:- configuration, i,e. the conversion of compounds derived from natural sources or from known totally synthetic procedures into compounds of the l8-epi-series, either accord ing to the above-described alcoholysis or the previously shown hydrolysis to the desired l8a-hydroXy-3-epi-alloyohimbane l6-carboXylic acid esters used as intermediates in the etherification procedure.

Especially important intermediates are the compounds of the formula:

in which R represents lower alkyl, and R stands for lower alkoxy, which substituents have been defined more extensively hereinbefore, and in which bromo is preferably located in the 4-position of the phenyl portion of the 18,8-(halogeno-phenyl)-sulfonyloxy group, and acid addition salts of such compounds. Members of this group are the lower alkyl IS-O-(bromo-p-henyl)-sulfonyl-reserpates, e.g. methyl 18-O-(4-bromo phenyl)-sulfonyl-reserpate, ethyl l8-O-(4-brorno-phenyl)-sulfonyl-reserpate, npropyl l8-O'-(4-bromo-phenyl)-sulfonyl-reserpate and the like, lower alkyl 18-O-(-brorno-phenyl)-sulfonyl-lO-methoxy-deserpidate, e.g. methyl 18-O-(4-bromo-phenyl)-sulfonyl-lO-methoxy-deserpidate, ethyl l8-O-(4-bromo-phenyl)-sulfonyl-IO-methoxy-deserpidate and the like, or any other analogous compound having the above formula.

Other important intermediates are, for example, lower alkyl 18-O-(brorno phenyl)-sulfonyl-deserpidates, e.g. methyl l8-O-(4-brorno-phenyl)-sulfonyl-deserpidate, ethyl 18-0-(4-bromo-phenyl)-sulfonyl-deserpidate and the like, as well as other lower alkyl 18-O-(bromo-phenyl)-sultonyl-deserpidate compounds useful as intermediates for 22 the preparation of the previously mentioned lower alkyl l8-epi-deserpidate compounds.

Another group of important intermediates used for the conversion of compounds with the 18B-configuration into derivatives of the l8a-series are those of the formula:

in which R stands for lower alkyl, and R represents lower alkoxy, which substituents have been described more closely hereinbefore, and in which the nitro group is preferably located in the 3- or 4-position of the phenyl portion of the 18B-(nitro-phenyl)-sulfonyloxy substituent, and acid addition salts of such compounds. Members of this group of compounds are the lower alkyl 18-O- (nitro-phenyl)-sulfonyl-reserpates, e.g. methyl 18-0-(4- nitro-phenyl)-su1fonyl-reserpate, methyl l8-O-(3-nitrophenyl)-sulfonyl-reserpate, ethyl 18-O-(4-nitro-phenyl)- sulfonyl-reserpate, ethyl l8-O-(3-nitro phenyl)-sultonylreserp-ate, n-propy-l 1 8-0-( 4-nitro-phenyl -sulfonyl-reserpate, n-propyl 18-O-(3-nitro-phenyl)-sulfonyl-reserpate, isopropyl l8-O-(4-nitro-phenyl)-sulfonyl-reserpate, isopropyl l8-0-(3-nitro-phenyl)-sulfonyl-resenpate and the like, lower alkyl 10-methoxy-18-O-(nitro-phenyl)-deserpidate, e.g. methyl IO-methoxy-l8-O-(4-nitro-phenyl)-sulfonyl-deserpidate, methyl lO-methoXy-l8-O-(3-nitro-phenyl)-sulfonyl-deserpidate, ethyl lO-methoxy-l8-O-(4-nitrophenyl)-sultonyl-deserpidate, ethyl l0-methoXy-18-O-(3- nitro-phenyl)-sulfonyl-desenpidate, n-propyl IO-methoxyl8-O-(4-nitro-phenyl)-sulfonyl-deserpidate, n-propyl l0- methoxy- 1 8-0- 3-nitro-phenyl) -sulfonyl-deserpidate, isoprop yl lO-methoxy- 1 8-0- (4-nitro-phenyl -sul-fonyl-deserpidate, isopropyl IO-methoxy-l 8-O-(3-nitro-pheny1)-sulfonyl-deserpidate and the like, or any other compound having the above formula.

Other important intermediates are, for example, lower alkyl lS-O-(nitro phenyl) sultonyl-deserpidates, e.g. methyl l8-G-(3-nitro-phenyl)-sulfonyl-deserpidate, methyl l8-O-(4-nitro-phenyl)-sulfonyl-deserpidate, ethyl 18-O- (3-nitro-phenyl)-sulfonyl-deserpidate, ethyl l8-O-(4-nitro-phenyl -sultonyl-deserpidate, n-propyl 1 8-0-( 3-nitrophenyl) sulfonyl deserpidate, n-propyl l8-O-(4-nitrophenyl)-sulfonyl-deserpidate, isopropyl 18-O-(3-nitrophenyl)-sulfonyl-deserpidate, isopropyl 18-O-(4-nitrophenyl)-sulfonyl-deserpidate, and the like, as well as other lower alkyl 18-0-(nitro-phenyl)sultonyl-deserpidate compounds useful as intermediates for the preparation of the previously mentioned lower alkyl l8-epi-deseipidate compounds.

The compounds of the present invention may also be prepared by removing in a A -lS-etheriiied hydroXy-alloyohimbene 16p-carboXy-lic acid ester or a salt of such compound, particularly in a compound having one of the formulae:

in R1, R2, R3, R4, R5, R and R7 have the previously given meaning, and in which a double bond extends from the 3-position, or salts thereof, the double bond extending from the 3-position by reduction and, if desired, carrying out the optional steps.

In the above'starting materials the double bond extends probably from the 3-position to the l4-position, or, in the salts thereof, from the 3-position to the 4-position. The anion in the above-mentioned salts stands primarily for the anion of a strong inorganic acid, particularly a mineral acid, such as a hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like, or phosphoric acid, a halogeno phosphoric acid, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable acid. It may also represent the anion of an organic acid; a salt with an organic acid may be present whenever a solution of the starting material in an organic acid, e.g. acetic acid and the like, is used in the above-described removal procedure.

The removal of the double bond may be carried out by reduction, particularly by treating a solution of the starting material in an acid, such as, for example, acetic acid (preferably in the form of aqueous acetic acid), perchloric acid and the like, with a metal. Together with the acid, the metal furnishes the reducing reagent capable of reducing the double bond; zinc, in the presence of an acid, e.g. acetic, perchloric acid and the like, yields a very useful reducing reagent. Zinc in the presence of perchloric acid, which may be used in an aqueous mixture or in admixture with another acid, e.g. acetic acid, represents the preferred reagent; this reagent is particularly suitable, because the rate of reduction is fast and any contact of the starting material, as 'well as the reduction product with the acidic medium can be kept to a minimum. Organic diluents, such as ethers, e.g. tetrahydrofuran, p-dioxan and the like, lower alkanones, e.g. acetone and the like, or any other suitable solvent may be present as additional diluents, if desired, together with water. The reduction may be carried out at room temperature, or, if necessary, under cooling or at an' elevated temperature.

The product of the reduction procedure may be isolated, for example, by neutralizing the acidic reaction mixture with an alkaline reagent, e.g. ammonia and the like, if desired, after removing the solvent or part of it, and extracting the organic material with a suitable solvent, e.g. methylene chloride and the like, or by any other appropriate isolation method.

The above procedure may be illustrated, for example, by the treatment of a lower alkyl l8-O-lower alkyl-A dehydro-reserpate, e.g. methyl l8-O-methyl-A -dehydroreserpate, methyl l8-O-ethyl-A3-dehydro-reserpate and the like, or of a lower alkyl l8-epi-O-lower alkyl-A dehydro-rcserpate, e.g. methyl l8-epi-O-methyl-A -dehydro-reserpate, methyl 1S-epi-O-ethyl-A -dehydro-reserpate, methyl l8-epi-O-n-propyl-A -dehydro-reserpate and the like, in which the double bond extends from the 3-position, or a salt thereof, with zinc in the presence of an acid, e.g. acetic, perchloric acid and the like, and isolation of the desired lower alkyl l8-O-lower alkyl-reserpates, e.g. methyl IS-O-methyI-reserpate, methyl l8-O-ethylreserpate and the like, and lower alkyl l8-epi-O-lower 24 alkyl-reserpates, e.g. methyl l8-epi-O-methyl-reserpate, methyl l8-epi-O-ethyl-reserpate, methyl 18-epi-O-npropyl-reserpate and the like.

The starting materials, which are used in the above procedure and have the previously given formula, are new and are intended to be included within the scope of the present invention. A preferred group of starting materials having the previously given formula, may be represented by the compounds of the formula:

in which each of the groups R and R stands for lower alkyl, containing preferably from one to four carbon atoms, e.g. methyl ethyl, n-propyl, isopropyl, n-butyl and the like, and R stands for lower alkoxy, containing preferably from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, n-butyloxy and the like, whereby R is preferably attached to the 10- position or the ll-position, and in which a double bond extends from the 3-position to the 14-position, and salts of such compounds, in which a double bond extends from the 3-position to the 4-position, especially salts containing as the anion portion an anion derived from an inorganic, particularly a mineral, acid, such as one of those mentioned hereinabove, e.g. hydrohalic acids, e.g. hydrochloric, hydrobromic acid and the like, phosphoric acid, halogeno-phosphoric acids, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable inorganic acid, as well as organic acids, e.g. acetic acid and the like. Specific compounds of this group of starting materials are, for example,

lower alkyl 18-O-lower alkyl-a -dehydro-rescrpates, e.g.

methyl l8-O-methyl-A -dehydro-reserpate,

methyl 18-O-ethyl-M-dehydro-reserpate,

methyl 18-O-n-propyl-A -dehydro-reserpate,

methyl l8-O-isopropyl-A -dehydro-reserpate,

methyl l8-O-n-butyl-A -dehydro-reserpate,

ethyl 18-O-methyl-A -dehydro-reserpate,

ethyl 18-0ethyl-A -dehydro-reserpate,

n-propyl l8-O-methyl-A -dehydro-reserpate,

isopropyl l8-O-methyl-A -dehydro-reserpate,

n-butyl 1S-O-methyl-a -dehydro-reserpate and the like,

lower alkyl 18-O-lower alkyl-10-methoxy-M-dehydto deserpidates, e.g.

methyl l0-methoxy-18-O-methyl-A -dehydro-deserpidate,

methyl l8-O-ethyl-10-methoxy-A -dehydrodeserpidate,

methyl lS-O-n-butyl-l0-methoxy-A -dehydro-deserpidate,

ethyl IO-methoxy-l8-O-rnethyl-A -dehydro-deserpidate,

ethyl l0-methoxy-l8-O-n-propyl-A -dehydro-deserpidate,

n-propyl IO-methoxy-l8-O-methyl-A -dehydrodeserpidate,

isopropyl lO-methoxy-l8-0-methyl-A -dehydrodeserpidate and the like,

in which compounds the double bond probably extends from the 3-position to the l4-position, and salts of such compounds, in which the double bond extends from the 3-position to the 4-position, as well as lower alkyl l8-O-l0wer alkyl-9-methoxy-A -dehydroreserpates, e.g.

methyl 9-methoxy-l 8-O-methyl-A -dehydro-deserpidate,

methyl l8-O-ethyl-9-methoxy-A -dehydro-deserpidate,

ethyl 9-lrnethoxy-l8-0-methyl-a -dehydro-deserpidate and t eli e,

lower alkyl ll-ethoxy-lS-O-lower alkyl-A -dehydrodeserpidates, e.g.

methyl 1 l-ethoxy-18-O-methyl-A -dehydro-desperidate,

methyl llethoxy-l8-O-ethyl-A -dehydro-desperidate,

n-propyl 1 l-ethoxyl 8-O-methyl-A -dehydro-deserpidate and the like,

lower alkyl 18-O-lowe1' alkyl-1l-n-propyloxy-A -dehydrodeserpidates, e.g.

methyl 18-O-methyll l-n-propyloxy-M-dehydrodeserpidate,

methyl l8-O-ethyl-l l-n-propyloxy-M-dehydro-deserpidate,

ethyl lS-O-methyI-l l-n-propyloxy-A -dehydro-deserpidate and the like,

lower alkyl ll-isopropyloxy-l8-O-lower alkyl-N-dehydrodeserpidates, e.g.

methyl 1 l-isopropyloxyl 8-O-methyl-M-dehydrodeserpidate,

methyl 1 l-isopropyloxy-l 8-O-n-propyl-A -dehydrodeserpidate,

ethel-l l-isopropyloXyl 8=O-methyl-A -dehydrodeserpidate and the like,

lower alkyl l1-n-butyloxy-18-O lower alkyl-A -dehydro deserpidates, e.g.

methyl 1 l-n-butyloxy-l 8-O-methyl-A -dehydrodeserpidate,

methyl 1 l-n-butyloXy-l 8-O-ethyl-M-dehydro-deserpidate,

n-propyl l l-n-butyloxy-l8-O-methyl-A -dehyd1'odeserpidate and the like,

lower alkyl l8-O-lower alkyl-12-methoXy-A -dehydrodeserpidates, e. g.

methyl l2-methoxy-l 8-O-methyl-A -dehydro-deserpidate,

ethyl lZ-methoxyl S-O-n-propyl-A -dehydro-deserpidate and the like,

in which compounds the double bond probably extendsfrom the 3-position to the l4-position, and salts of these compounds, in which the double bond extends from the 3-position to the 4-position.

Another group of very useful intermediates are, for example,

lower alkyl 18-O-lower alkyl-A -dehydro-deserpidates, e.g.

methyl 18-O-methyl-A -dehydro-deserpidate, methyl 18-O-ethyl-A -dehydro-deserpidate, methyl 18-O-n-butyl-A -dehydro-deserpidate, ethyl l8 O-methyl-A -dehydro-deserpidate, ethyl l8-O-n-propyl-A -dehydro-deserpidate, n-propyl l8-O-methyl-A -dehydro-deserpidate, isopropyl l8-O-methyl-A -dehydro-deserpidate,

n-butyl18-O-methyl-A -dehydro-deserpidate and the like,

in which compounds the double bond probably extends from the 3-position to the l4-position, and the salts of those of the previously mentioned acids, particularly'those of inorganic acids.

Additional important intermediates useful in the above procedure are, for example, lower alkyl 18-O-lower alkyl- S-methyI-A -dehydrO-reserpates,

lower alkyl 18-O-lower alkyl-9-methyl-A -dehydrodeserpidates,

e.g.' methyl 9-methyl1-8-O-rnethyl-A -dehydro-deserpidate,

methyl l8-O-isopropyl-9-methyl-A -dehydro-deserpidate,

methyl 9-methyl-18-O-n1ethyl-A -dehydro-deserpidate and the like,

lower alkyl l8-O lower alkyl-ll-methyl-M-dehydrodeserpidates,

e. g. methyl 1l-methyl-l8-O-methyl-A -dehydrodeserpidate,

methyl IS-O-ethyl-l l-methyl-M-dehydro-deserpidate,

ethyl 11-methyl-l8-O-methyl-h -dehydro-deserpidate and the like,

lower alkyl 18-O-lower alkyl-IO-methoxy-M-dehydrov reserpates,

e.g. methyl IO-methoxy-18-O-methyl-A -dehydroreserpate,

methyl lS-O-ethyl-10-methoxy-A -dehydro-reserpate,

n-propyl 1O-methoxy-l8-O-methyl-A -dehydro-reserpate and the like,

'lower alkyl 9,10-dimethoxy-l8-O-lower alkyl-M-dehydro reserpates,

e.g. methyl 9,10-dimethoxy-l8-O-methyl-A -dehydroreserpate,

methyl 9,IO-dimethoXy-l8-O-ethyl-A -dehydro-reserpate,

ethyl 9,10-dimethoxy-l8-O-methyl-A -dehydro-reserpate and the like,

lower alkyl 18-O-lower alkyl-10,1l-methylenedioxy-A dehydro-deserpidates,

e.g. methyl l8-O-methyl-l0,l1-methylenedioxy-A -dehydro-deserpidate,

methyl 10,1 l-methylenedioXy-l 8-O-n-propyl-A -dehydrodeserpidate,

ethyl 18- O-methyl-10,l 1-methylenedioXy-A -dehydrodeserpidate and the like,

lower alkyl l8-O-lower alkyl-l1-methylme1'capto-A -dehydro-deserpidates, r

e.g. methyl 18-O-methyl-1l-methylmercapto-A -dehydrodeserpidate,

methyl 18-O-ethyl-ll-methylmercapto-A -dehydrodesirpidate,

n-propyl 18-O-methyl-l1-methylmercapto-A -dehyd1'odeserpidate and the like,

lower alkyl ll-ethylmarcapto-lS-O-lower alkyl-h -dehydro-deserpidates,

e,g. methyl ll-ethylmarcapto-l8-O-methyl-A -dehydrodeserpidate,

methyl IS-O-ethyl-ll-ethylmercapto-A -dehydrodeserpidate,

ethyl ll-ethylmarcapto-l8-O-methyl-A -dehydrodeserpidate and the like,

lower alkyl 1l-fiuor0-l8-O-lower alkyl-A -dehydrodeserpidates,

e.g. methyl-l l-fluoro-l8-O-methyl-N-dehydro-deserpidate,

methyl ll-fiuoro-l8-O-n-propyl-A -dehydro-deserpidate,

isopropyl 1 l-fluoro-l 8-0-methyl-A -dehydro-deserpidate and the like,

lower alkyl lO-chloro-l8-O-l0wer alkyl-A -dehydrodeserpidates, I

.e. g. methyl lO-chloro-18-O-methyl-A -dehydrodeserpidate,

methyl lO-chloro-l8-O-ethyl-A -dehydro-deserpidate,

ethyl 1O-chloro-l8 0-methyl-A -dehydro-deserpidate and the like,

lower alkyl lO-bromo-lS-O-lower alkyl-A -dehydroreserpates,

e.g. methyl 1O-bromo-18-O-methyl-A -dehydro-reserpate,

methyl 1O-bromo-l8-O-ethyl-A -dehydro-reserpate,

ethyl IO-bromo-l8-O-methyl-A -dehydro-reserpate and the like,

lower alkyl 17tx-desmethoxy-17a-ethoxy-l8-O-lower alkyl- A -dehydro-reserpates,

e.g. methyl l7a-desmethoxy-17a-ethoXy-18-O-methyl-A dehydro-reserpate,

methyl l7u-desrnethoxy-17a-ethoxy-18-O-ethyl-A -dehydro-reserpate,

n-propyl l7a-desmethoxy-l7a-ethoxy-l8-O-methyl-A dehydro-reserpate and the like,

lower alkyl l7 a-desmethoxy-18-O-lower alkyl-l7a-n-propyloxy-A -dehydro-reserpates,

e.g. methyl l7m desmethoxy l8-O-methyl-17a-n-propyloxy-A -dehydro-reserpate,

methyl l7a-desmethoxy-18-O-n-propyl-l7u-n-propyloxy- A -dehydro-reserpate,

ethyl l7a-desmethoxy-lS-O-methyl-l7oa-n-propyloxy-A dehydro-reserpate and the like,

lower alkyl l7a-desmethoxy-17a-ethoxy-l8 O-lower alkyl- N-dehydrmreserpidates,

e.g. methyl l7u-desmethoxy-17a-ethoxy-l8-O-methyl-A dehydro-deserpidate,

methyl 17a-desmcthoxy-17a-ethoxy-18-O-n-propyl-A dehydro-desirpidate;

ethyl l7a-desmethoxy-l7a-ethoxy-18-O-methyl-A -dehydro-deserpidate and the like,

lower alkyl 17a-cyano-17a-desmethoxy-l8-O-lower alkyl- A -dehydro-reserpates,

e.g. methyl 17a-cyano-l7a-desmethoxy-l8-O-methy1-A dehydro-reserpate,

methyl 17u-cyano-17u-desmethoxy-l8-O-ethyl-A -dehydroreserpate,

ethyl 17d-cyano-17a-desmethoxy-18-O-methyl-A -dehydroreserpate and the like,

lower alkyl l7a-cyano-17rx-desmethoxy-18-O-lower alkyl- A -dehydro-deserpidates,

e.g. methyl 17a-cyano-17a-desmethoxy-l8-O-methyl-A dehydro-deserpidate,

methyl 17u-cyano-17a-desmethoxy-18-O-n-propyl-A -dehydro-deserpidate,

n-propyl 17a-cyan0-l7a-desmethoxy-18-O-methyl-A -dehydro-deserpidate and the like,

or analogous compounds, in which the double bond probably extends from the 3-position to the 14-position, and salts of these compounds, in which the double bond extends'from the 3-position to the 4-position. Upon reduction of the double bond extending from the 3-position, these compounds can be converted into the desired compounds of this invention.

An additional group of important compounds may be represented by the formula:

in which each of the groups R and R stands for lower alkyl, containing preferably from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, and' R stands for lower alkoxy, containing preferably from one to four carbon atoms, particularly methoxy, as well as ethoxy, n-propyloxy, n-butyloxy and the like, whereby R is preferably attached to the IO-position or the ll-position, and in which a double bond extends from the 3-position to the '14 position, and salts of such compounds, in which a double bond extends from the 3-position to the 4-position, especially salts containing as the anion portion an anion derived from an inorganic, particularly a mineral, acid, such as one of those mentioned hereinabove, e.g. hydrohalic acids, e.g. hydrochloric, hydrobromic acid and the like, phosphoric acid, halogeno-phosphoric acids, e.g. chlorophosphoric acid and the like, or perchloric acid or any other suitable inorganic acid, as well as organic acids, e.g.

28 acetic acid and the like. Specific compounds of this group of starting materials are, for example, lower alkyl l8-epi-O-lower alkyl-A -dehydr0-reserpates,

e.g. methyl l8-epi-O-methyl-A -dehydro-reserpate,

methyl 18-epi-O-ethyl-A -dehydro-reserpate,

methyl 18-epi-O-n-propyl-A -dehydro'reserpate,

methyl l8-epi-O-isopropyl-A -dehydro-reserpate,

methyl l8-epi-O-n-butyl-M-dehydro-reserpate,

ethyl 18-epi-O-methyl-N-dehydro-reserpate,

ethyl 1S-epi-O-ethyl-A -dehydro-reserpate,

n-propyl 18-epi-O-methyl-A -dehydro-reserpate,

n-propyl l8-epi-O-ethyl-A -dehydro-reserpate,

isopropyl 18-epi-O-methyl-A -dehydro-reserpate,

n-butyl 18-epi-O-methyl-A -dehydro-reserpate,

isobutyl l8-epi-O-methyl-M-dehydro-reserpate,

n-pentyl l8-epi-O-ethyl-A -dehydro-reserpate and the like,

lower alkyl 18-epi-O-lower alkyl-10-methoxy-M-dehydrodeserpidates,

e.g. methyl 10-methoxy-l8-epi-O-methyl-M-dehydrodeserpidate,

methyl 18-epi-O-ethy1-10-methoxy-A -dehydro-deserpidate,

methyl IO-methoxy-l8-epi-O-n-propyl-A -dehydrodeserpidate,

methyl 1 8-epi-O-isopropyl- 1 O-methoxy-M-dehydrm deserpidate,

ethyl lO-methoxy-l8-epi-O-methyl-A -dehydro-deserpidate,

n-propyl IO-methoxy-l8-epi-O-methyl-A -dehydrodeserpidate,

n-propyl IS-epi-O-ethyll O-methoxy-M-dehydrodeserpidate,

isopropyl 10-methoxy l8-epi-O-methyl-A -dehydrodeserpidate and the like,

in which compounds the double bond probably extends from the 3-position to the l4-position, and salts of such compounds, in which the double bond extends from the 3-position to the 4-position, as well as lower alkyl 18-epi-O-lower alkyl-9-methoxy-A -dehydro-deserpidates,

e.g. methyl 9-methoxy-l8-epi-O-methyl-A -dehydrodeserpidate,

methyl l8-epi-O-ethyl-9-methoxy-A -dehydro-deserpidate,

methyl 9-methoxy-18-epi-O-n-propyl-A -dehydrodeserpidate,

ethyl 9-methoxy-18-epi-O-methyl-A -dehydro-deserpidate and the like,

lower alkyl ll-ethoxy-lS-epi-O-lower alkyl-A -dehydrodeserpidates,

e.g. methyl 1l-ethoxy-l8-epi-O-methylA -dehydrodeserpidate,

methyl 1 l-ethoxy-l 8-epi-O-ethyl-A -dehydro-deserpidate and the like,

lower alkyl 18-epi-O-lower alkyl-ll-n-propyloxy-A -dehydro-deserpidates,

e.g. methyl 18-epi-O-methyl-l1-n-propyloxy-A -dehydrodeserpidate,

methyl IS-epi-O-ethyl-l l-n-propyloxy-A -dehydrodeserpidate and the like,

lower alkyl 1l-isopropyloxy-l8-epi-O-lower alkyl-A dehydro-deserpidates,

e.g. methyl 1l-isopropyloxy-l8-epi-O-methyl-A -dehydrodeserpidate,

methyl 1-8-epi-O-ethyl-l1-isopropyloxy-A -dehydrodeserpidate and the like,

lower alkyl ll-n-butyloxy-l8epi-O-lower alkyl-A -dehydro-deserpidates,

e.g. methyl 1l-n-butyloxy-l8-epi-Omethyl-A -dehydrodeserpidate,

methyl 11-n-butyloxy-18-epi-O-ethyl-deserpidate and the like,

lower alkyl 18-epi-O-lower alkyl-l2-methoxy-A -dehydrodeserpidates,

e.g. methyl 12-methoxy-18-epi-O-methy1-A -dchydrodeserpidate,

29 methyl lS-epi-O-ethyl-12-methoxy A -dehydro-deserpidate, ethyl lS-epi-O-ethyl-l2-methoxy-A -dehydro-deserpidate and the like,

in which compounds the double bond extends probably from the 3-position to the l4-position, or salts thereof, in which the double bond extends from the 3-position to the 4-position.

An additional preferred group of compounds are the lower alkyl l8-epi-O-lower alkyl-A -dehydro-deserpidates, in which lower alkyl contains preferably from one to four carbon atoms, and is represented primarily by methyl, as well as ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, in which compounds the double bond extends probably from the 3-position to the 14-position, and salts thereof, in which the double bond extends from the 3-position to the 4-position. Specific members of this group are, for example,

methyl l8-epi-O-methyl-A -dehydro-deserpidate,

methyl 18-epi-O-ethyl-M-dehydro-deserpidate,

methyl 1S-epi-O-n-propyl-M-dehydro-deserpidate,

methyl l8-epi-O-isopropyl-A -dehydro-deserpidate,

methyl 1-8-epi-O-n-butyl-A -dehydro-deserpidate,

methyl l8-epi-O-secondary butyl-A -dehydro-deserpidate,

ethyl l8-epi-O-methyl-A -dehydro-deserpidate,

ethyl l8-epi-O-ethyl-A -dehydro-deserpidate,

ethyl lS-epi-O-11-propyl-A -dehydro-deserpidate,

n-propyl l8-epi-Oethyl-A -dehydro-deserpidate,

n-propyl l8-epi-O-ethyl-A -dehydro-deserpidate,

isopropyl l8-epi-O-rnethyl-A -dehydro-deserpidate,

isopropyl l8-epi-O-n-butyl-A -dehydro-deserpidate,

n-butyl l8-epi-O-methyl-A -dehydro-deserpidate,

secondary butyl l8-epi-O-methyl-A -dehydro-deserpidate,

n-pentyl l8-epi-O-methyl-A -dehydro-deserpidate and the like.

Other compounds which may be used as intermediates in the above procedure are, for example, lower alkyl l8-epi-O-lower alkyl-5-methyl-A -dehydro-reserpates,

e.g. methyl S-methyl-l8-epi-O-methyl-A -dehydroreserpate,

methyl 18-epi-O-ethyl-S-methyl-A -dehydro-reserpate,

ethyl S-methyl-lS-epi-O-methyl-A -dehydro-reserpate and the like,

lower alkyl 18-epi-O-lower alkyl-6-methyl-A -dehydroreserpates,

e.g. methyl 6-methyl-l8-epi-O-methyl-A -dehydroreserpate,

methyl 18-epi-Oethyl-6-methyl-M-dehydro-reserpate,

ethyl 6-methyl-l8-epi-O-n-propyl-A -dehydro-reserpate and the like,

lower alkyl l8-epi-O-lower alkyl-6-methyl-A -dehydrodeserpidates,

e.g. methyl 6-methyl-1S-epi-O-methyl-A -dehydrodeserpidate,

methyl 6-methy1-lS-epi-O-n-propyl-M-dehydrodeserpidate,

ethyl lS-epi-O-isopropyl-6-methyl-A -dehydro-deserpidate and the like,

lower alkyl 18-epi-O-lower alkyl-9-methyl-A -dehydrodeserpidates,

e.g. methyl 9-methyl-l8-epi-O-methyl-A -dehydrodeserpidate,

methyl 9-methyl-l8-epi-o-ethyl-A -dehydro-deserpidate,

n-propyl l8-epi-O-ethyl-9-methyl-A -dehydro-deserpidate and the like,

lower alkyl l8-epi-O-lower alkyl-ll-methyl-A -dehydrodeserpidates,

e.g. methyl 1l-methyl-l8-epi-O-methyl-A -dehydrodeserpidate,

methyl l8-epi-O-ethyl-ll-methyl-A -dehydro-deserpidate,

ethyl ll-methyl-l8-epi-O-n-propyl-A -dehydro-deserpidate and the like,

lower alkyl 1-8-epi-O-lower alkyl-lO-methoxy-M-dehydroreserpates, 1

e.g. methyl l0-methoxy-l8-epi-O-methylA -dehydro- V reserpate,

methyl lS-epi-O-ethyl-lO-methoxy-A dehydro-reserpate,

ethyl lO-methoxy-l8-epi-O-n-propyl-A -dehydro-reserpate and the like,

lower alkyl 9,l0-dimethoxy-l8-epi-O-lower alkyl-A -dehydro-reserpates,

e.g. methyl 9,10-dimethoxy-l8-epi-O-methyl-A -dehydroreserpate,

methyl 9,IO-dimethoxy-l8-epi-O-ethyl-A -dehydroreserpate,

n-propyl 9,10-dimethoxy-18-epi-O-ethyl-A -dihydroreserpate and the like, a

lower alkyl 18-epi-O-lower alkyl-10,11-lower alkylenedioxy-A -dehydro-deserpidates,

e.g. methyl 18-epi-O-methyl-l0,ll-methylenedioxy-M- dehydro-deserpidate,

methyl l8-epi-O-ethyl-10,11-methylenedioxy-A -dehydrodeserpidate and the like,

lower alkyl lO-benzyloxy-l8-epi-O-lower alkyl-A -dehydrodeserpidates,

e.g. methyl IO-benzyloxy-l8-epi-O-methyl-A -dehydro deserpidate,

methyl 1O-benzyloxy-l8-epi-O-ethyl-A -dehydrodeserpidate,

ethyl lO-benzyloxy-l8-epi-O-methyl-M-dehydrodeserpidate and the like,

lower alkyl ll-benzyloxy-l8-epi-O-lower alkyl-A dehydro-deserpidates,

e. g. methyl ll-benzyloxy-l8-epi-O-methyl-A -dehydrodeserpidate,

methyl ll benzyloxy-l8-epi-O-ethyl-A -dehydrodeserpidate,

ethyl 1l-benzyloxy-l8-epi-O-methyl-A -dehydrodeserpidate and the like,

lower alkyl l8-epi-O-lower alkyl-ll-methylmercapto-A dehydro-deserpidates, I

e.g. methyl l8epi-O-methyl-ll-methylmercapto-A -dehydro-deserpidate,

methyl l8-epi-O-ethyl-l 1-methylmercapto-A -dehydro deserpidate,

ethyl l8-epi-O-methyl-ll-methylmercapto-M-dehydrodeserpidate and the like,

lower alkyl ll-ethylmercapto-l8-epi-O-lower alkyl-A dehydro-reserpidates,

e.g. methyl ll-ethylmercapto-l8-epi-O-methyl-A -dehydrodeserpidate,

ethyl IS-epi-O-ethyl-l 1-ethylmercapto-A -dehydrodeserpidate,

n-propyl 1l-ethylmercapto-l8-epi-O-n-propyl-A -dehydrodeserpidate and the like,

lower alkyl lO-chloro-lS-epi-O-powr alkyl-A -dehydrodeserpidate,

e.g. methyl lO-chloro-l8-epi-O-methyl-A -dehydrodeserpidate,

methyl 10-chloro-18-epi-O-ethy1-M-dehydro-deserpidate,

ethyl lO-chloro-18-epi-O-n-butyl-A -dehydro-deserpidate and the like,

lower alkyl ll-fluoro-lB-epi-O-lower alkyl-A -dehydrodeserpidates,

e.g. methyl ll-fluoro-l8-epi-O-methyl-A -dehydrodeserpidate,

methyl ll-fluoro-l8-epi-O-n-propyl-A -dehydrodcserpidate,

ethyl 1 l-fluoro-l 8-epi-O-isopropyl-A -dehydro-deserpidate and the like,

lower alkyl lO-bromo-18-epi-O-lower alkyl-A -dehydroreserpates,

e.g. methyl 1O-bromo-18-epi-O-methyl-A -dehydroreserpate,

methyl 10-bromo-l8-epi-O-ethyl-A -dehydro-reserpate,

ethyl lO-bromo-l8-epi-O-ethyl-M-dehydro-reserpate and the like,

lower alkyl l7a-desmethoxy-l7ot-ethoxy-l8-epi-0-1ower alkyl-A -dehydro-reserpates,

e.g. methyl l7u-desmethoxy-17a-ethoxy-1S-epi-O-methyl- A -dehydro-reserpate,

methyl 17a-desmethoxy-17a-ethoxy-18-epi-O-ethyl-A dehydro-reserpate and the like,

lower alkyl l7a-desmethoxy-18-epi-O-lower alkyl-l7u-npropyloxy-A -dehydro-reserpate,

e.g. methyl 17a-desmethoxy-1S-epi-O-methyl-lh-n-propyloxy-A -dehydro-reserpate,

ethyl 17a-desmethoxy-l8-epi-O-n-propyl-17a-n-propyloxy- A -dehydro-reserpate and the like,

lower alkyl 1 7a-desmethoxy- 17u-isopropyloxy-18-epi-O- lower alkyl-M-dehydro-reserpates,

e.g. methyl 17a-desmethoxy-17a-isopropyloxy-l8-epi-O- methyl-reserpate,

methyl 17a-desmethoxy-lS-epi-O-ethyl-17x-isopr0pyloxy- A -dehydro-reserpate and the like,

lower alkyl l7a-desmethoxy-l7a-ethoxy-18-epi-O-lower alkyl-M-dehydro-deserpidate,

e.g. methyl l7a-desmethoxy-l7u-ethoxy-l8-epi-O-methyl- A -dehydro-deserpidate,

methyl 17a-desmethoxy-17a-ethoxy-18-epi-O-ethyl-A dehydro-deserpidate,

ethyl 17a-desmethoxy-17a-ethoxy-l8-epi-O-ethyl-A -dehydro-deserpidate and the like,

lower alkyl 17a-cyano-l7a-desmethoxy-l8-epi-O-lower alkyl-A -dehydro-reserpates,

e.g. methyl 17a-cyano-l7a-desmethoxy-18-epi-O-ethyl-A dehydro-reserpate,

ethyl 17a-cyano-17a-desmethoxy-18-epi-O-methyl-A dehydro-reserpate and the like,

lower alkyl 17a-cyano-l7a-desmethoxy-l8-epi-O-lower alkyl-A -dehydro-deserpidates,

e.g. methyl l7u-cyano-17a-desmethoxy-18-epi-O-methyl- M-dehydro-deserpidate,

methyl 17a-cyano-l7a-desmethoxy-l8-epi-O-n-propyl-A dehydro-deserpidate,

n-propyl 17a-cyano l7a-desmethoxy-l8-epi-O-ethyl-A dehydro-deserpidate and the like,

in which compounds the double bond probably extends from the 3-position to the 14-position, and salts thereof, in which the double bond extends from the 3-position to the 4-position. The anions of the salts are those derived from inorganic or organic acids such as those described hereinbefore, e.g. hydrochloric, perchloric, chloro-phosphoric acid and the like.

In the above-described starting materials, the free compounds probably have the following partial formula:

i.e. the double bond extends from the 3-position to the 14-position, whereas the corresponding salts have the partial formula:

in which R R R R R R and R have the previously given meaning, with a ring-closing reagent, and, if desired, converting a resulting salt into the free compound, and/ or, if desired, converting a free compound into a salt thereof.

Ring closure of the above-described 2,3-seco-allo-yohimbane compounds may be carried out according to known methods, for example, by treatment with an acidic ring closing reagent, for example, a phosphoric acid, e.g. polyphosphoric acid and the like, a phosphorus halide, e.g. phosphonis trichloride, phosphorus pentachloride, or advantageously a phosphorus oxyhalide, e.g. phosphorus oxychloride and the like.

The 2,3-seco-allo-yohimbane compounds used as the intermediates in the preparation of the A -allo-yohimbane starting materials may be prepared according to difierent procedures. For example, in an 18-hydroxy-3-oxo-2,3- seco-allo-yohimbane 16-carboxylic acid ester, particularly in a compound having one of the formulae:

in which R R R R R and R have the previously given meaning, the free hydroxyl group may be etherified. Etherification may be carried out according to the previously mentioned etherification procedure described in detail; lower diazo-alkanes, e.g. diazomethane, diazoethane and the like, in the presence of fluoboric acid or any other suitable Lewis acid are the preferred reagents. Etherification may also be achieved according to other known procedures, for example, by treatment with other reagents suitable for the etherification of a secondary hydroxyl group. Such reagents are, for example, reactive esters formed by aliphatic hydroxy-hydrocarbon compounds, such as lower alkanols, particularly methanol, as well as ethanol and the like, or by substituted aliphatic hydroxy-hydrocarbon compounds with strong acids, such as inorganic acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like, or with organic acids, particularly strong organic sulfonic acids, e.g. p-toluene sulfonic acid and the like, which reagents are preferably used in the presence of reagents facilitating the etherification procedure. Especially useful are di-lower alkyl sulfates, such as dimethyl sulfate, cliethyl sulfate and the like, which reagents are preferably used in the presence of a base, such as an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, lower alkyl halides, such as methyl, ethyl, n-propyl or n-butyl chloride, bromide or iodide and the like, which reagents are preferably used in the presence of a basic reagent, such as, for example, silver oxide and the like, or any other suitable etherification procedure.

The above etherification procedure is particularly suitable for the preparation of 3-oxo-2,3-seco-alloy-yohimbane compounds with an 18-ether group having the fi-configuration, i.e. compounds which can be prepared directly from products obtained according to known totally synthetic methods.

The intermediate 3-oxo-2,3-seco-allo-yohirnbane compounds may also be prepared by esterifying in an 18- hydroxy-3-oxo-2,3-seco-allo-yohimbane 16-carboxylic acid ester, particularly in a compound having one of the previously given formulae, the free hydroxyl group, by treatment with an organic sulfonic acid halide, such as a carbocyclic aryl sulfonyl halide, particularly a monocyclic carbocyclic aryl sulfonyl halide, as well as an aliphatic sulfonic acid halide, for example, a compound of the formula RSO I-Ial, in which R has the previously given meaning and Hal stands for halogeno, particularly chloro and treating a resulting 18-organic sulfonyloxy- 3-oxo-2,3-seco-allo-yohimbane 16- carboxylic acid ester, particularly a compound having one of the formulae:

1 ll H in which R R R R R R and R have the previously given meaning, with an organic hydroxylated compound, particularly a compound of the formula R -OH, in which R has the previously given meaning. Esterification with an organic sulfonic acid halide, for example,

with a (halogeno-phenyl)-sulfonyl chloride or a (nitrophenyl)-sulfonyl chloride, is carried out as previously shown, for example, in the presence of an organic base, e.g. pyridine and the like. Alcoholysis of the ester grouping may be achieved according to the procedure described hereinbefore; a lower alkanol, especially in the presence of an organic tertiary amine, e.g. N,N,N-diethylamine, pyridine and the like, represents the preferred reagent. As has been shown hereinbefore, alcoholysis of the 18-organic sulfonyloxy group causes inversion at the 18-carbon atom.

This procedure is particularly suitable for the preparation of 3-oxo-2,3'-seco-yohimbane compounds with an 18-ether grouping having the OC-COIIfigUI'HtiOII, i.e. compounds, which can be prepared through a procedure involving inversion using products obtained according to known totally synthetic methods.

The ISa-hYdIOXY 3 oxo-2,3-seco-allo-yohimbane 16- carboxylic acid esters, which compounds can be used either in the above etherification procedure to form the ISa-etherified hydroxy-3-oxo-2,3-seco-allo-yohimbane 16- carboxylic acid esters or in the esterification to the 18aorganic sulfonyloxy 3 oxo-2,3-seco-allo-yohimbane 16- carboxylic acid esters, may be obtained by hydrolysis of the 18,8-organic sulfonyloxy 3 oxo-2,3-seco-allo-yohimbane 16-carboxylic acid esters with water, preferably in the presence of an organic tertiary amine. Such hydrolysis procedure is carried out according to methods previously described in detail.

The lS-etherified hydroxy-3-oxo-2,3-seco-allo-yohimbane 16-carboxylic acid esters may also be prepared, for example, by ring closure of an 18-etherified hydroxy-3- lower alkoxy-3-oxo-2,3;3,4-bis-seco-allo-yohimbane 16- oanboxyli'c acid ester, particularly of a compound having one of the formulae:

35 9a,-10a-octahydro-naphthalene l-carboxylic acid ester, particularly a compound of the formula:

in which R and R have the previously given meaning, the free hydroxyl group according to previously given methods used for the etherification of secondary hydroxyl groups, to form a 3fl-etherified hydroxy-7-oxo-1,2;3,3u,4,7, 8,9a,la-octahydro-naphthalene l-carboxylic acid ester, particularly a compound of the formula:

in which R R and R have the previously given meaning. Or, a 3fi-hydroxy-7-oxo-1,2fl,3a,4,7,8,9a,IOa-octahydronaphthalene l-carboxylic acid ester, such as a compound having the above-given formula, may be reacted with an organic sulfonic acid halide, such as a compound of the formula RSO -Hal, in which R and Hal have the previously given meaning, preferably a monocyclic carbocyclic aryl-sulfonyl chloride, in the presence of an organic base, and treating a resulting BB-organic sulfonyloxy-7- 0x0 1,2}3,3a,4,7,8,9a,oc octahydro-naphthalene l-carboxylic acid ester, particularly the compound of the formula:

in which R R and R have the previously given meaning, with an organic hydroxylated compound, especially a compound of the formula R3-'OH, in which R has the previously given meaning, preferably in the presence of an organic tertiary base to form a Bu-etherified hydroxy-7- oxo 1,2/3,3 3,4,7,8,9a,lOa-octahydro-naphthalene l-carboxylic acid ester, particularly a compound of the formula:

in which R R and R have the previously given meaning. The above shown 3-etherified hydr0xy-7-oxo-l,2l9,3, 4,7,8,9u,lOa-octahydro-naphthalene l-carboxylic acid esters, having particularly the previously given formulae, are then oxidized, for example, with osmium tetroxide in an aqueous solution, followed by treatment with sodium chlorate, to form a 50,60t-dlhYdI'OXY-3-the1'ified hydroxy- 7-oxo 1,2;3,3,4,5fi,7,8,9a,10a decahydro-naphthalene l- 36 carboxylic acid ester, particularly a compound having one of the formula:

ment with periodic acid hydrate in an aqueous medium, to form a 5/3-aldehydo-3-etherified hydroxy-6B-carboxymethyl-1,2 3,3,4,5a,6a-hexahydro-benzene l-carboxylic acid ester, especially a compound having one of the formulae:

in which R R and R have the previously given meaning. The free carboxyl group of the carboxymethyl portion is then esterified, for example, with a lower diazoalkane, e.g. diazomethane, diazoethane and the like, to form the desired 5 3-aldehydo-3-etherified hydr0Xy-6B-carbo-lower alkoxy methyl-1,Zfl,3,4,5a,6a-hexahydro-benzene l-carboxylic acid ester, such as a compound having the formula:

in which R R and R have the previously given meaning, and R represents lower alkyl, particularly methyl, as Well as ethyl and the like. This compound is then reacted with a tryptamine, particularly a tryptamine compound of the formula:

in which R R R and R have the above-given meaning, preferably in solution with an inert solvent, e.g. benzene and the like, to yield a A -18-etherified hydroxy- 3-lower alkoxy-3-oxo-2,3;3,4-bis-seco-allo-yohimbane l6- carboxylic acid ester, particularly a compound having one of the formulae:

in which R R R R R R R and R7 have the previously given meaning. Upon treatment with a reducing reagent, for example, with a borohydride, e.g. sodium borohydride and the like, in an inert solvent, such as a lower alkanol, e.g. methanol, ethanol and the like, and, if necessary, in the presence of an activator, e.g. aluminum chloride and the like, the Schiif-base type double bond is reduced, and the desired lS-etherified hydroxy-3-lower alkoxy-3 -oxo-2,3 ;3 ,4-bis-seco-allo-yohimbane 16-carboxylic acid ester, is formed, in which the esterified carboxyl groups may be partially or totally hydrolyzed. Hydrolyzed carboxyl groups may subsequently be re-esterified (for example, by treatment with a lower aliphatic diazohydrocarbon, such as a lower diazoalkane, particularly diazomethane, as well as diazoethane and the like, or any other suitable diazo-reagent) The 5/3-aldehydo-3-etherified hydroxy-65-carbo-lower alkoxy-methyl-l,2 3,3 ,4,5a,6a-hexahydro benzene l-carboxylic acid ester, particularly a compound having one of the previously shown formulae, may also be prepared, for example, by directly etherifying or esterifying with an organic sulfonic acid halide and subsequently alcoholizing with an alcohol in a 3-hydroxy-7-oxo-l,2j8,3,4,7, 8,9a,l0u-octahydro-naphthalene l-carboxylic acid ester, particularly in a compound having one of the formulae:

in which R and R have the previously given meaning, the hydroxyl group attached to the 3-position, which reactions may be carried out according to the previously described methods. A resulting 3-etherified hydroxy-7- oxo-11,6,3,4,7,8,9a,9a,10a-octahydro naphthalene l-carboxylic acid ester, particularly a compound having one of the formulae:

in which R R and R have the previously given meaning, is then subjected to the treatment of ozone in the presence of an inert organic solvent, for example, in glacial acetic acid, ethyl acetate and the like, and at temperatures between about 0 and about 60 to effect ozonation, the excess ozone is removed from the reaction mixture, for example, by bubbling an inert gas, e.g. nitrogen and the like, through the reaction solution, and the resulting ozonide is decomposed by adding water at room temperature to form the desired Sfl-aldehydo-Iaetherified hydroxy-6B-carboxymethyl-1,2B,3,4,5a,6whexahydro-benzene l-carboxylic acid ester, particularly a compound having one of the formulae:

in which R R and R have the previously given meaning, in which compounds the free carboxyl group is then esterified as previously shown to yield the desired intermediate, which is condensed with the tryptamine compound.

The etherification of a free hydroxyl group, with or without simultaneous inversion, may also be carried out at any other suitable step of the above shown procedures leading to the desired intermediates for the preparation of the starting materials.

The A -l8-etherified hydroXy-allo-yohimbene 16-carboxylic acid esters or the salts thereof, which compounds are used as starting materials for the preparation of the l8-etherified hydroxy-3-epi-allo-yohimbane 16-carboxylic acid esters according to the previously described procedure, may also be prepared, for example, by ring closure of an 18-organic sulfonyloxy-3-oxo-2,3-seco-allo-yohimbane 16-carboxylic acid ester, particularly a compound having one of the previously shown formulae, and subsequent alcoholysis of a resulting A IS-organic sulfonyloxyallo-yohimbene 16-carboxylic acid ester, in which the double bond extends probably from the 3-position to the 14-position, or a salt thereof, in which the double bond extends from the 3-position to the 4-position, particularly of a compound having one of the formulae:

in which R R R R R R and R have the previously given meaning, and in which a double bond extends probably from the 3-position to the l4-position, or salts thereof, in which a double bond extends from the 3-position to the 4-position, to yield the desired starting materials, ie the A -18etherified hydroxy-allo-yohirnbene 16-carboxylic acid esters. Ring closure (preferably with phosphorus oxychloride) and alcoholysis (preferably with a lower alkanol in the presence of an organic tertiary amine) are carried out according to methods described in detail hereinbefore.

In the above methods for the preparation of the starting materials, new and important intermediates are being formed, which are intended to be included within the scope of this invention. Particularly useful are the 18- etherified hydroxy-3-oxo-2,3-seco-allo-yohirnbane l6-carboxylic acid esters, particularly one of the compounds having the previously shown formula. A preferred group of these intermediates is represented by the formula:

in which each of the radicals R and R have the previously given meaning, i.e. stand for lower alkyl, and R represents lower alkoxy as previously shown. This group is represented by the lower alkyl Other compounds of the aforementioned formula are, for example, the lower alkyl IS-O-lower alkyl-9-methoxy-3-oxo-2,3-seco-deserpidates,

e.g. methyl 9-methoxy-18-O-methyl-3-0xo-2,3-seco-deserpidate,

methyl 18-O-ethyl-9-methoXy-3 -oxo-2,3-seco-deserpidate,

ethyl 9-methoxy-18-O-methyl-3-oxo-2,3-seco deserpidate and the like,

lower alkyl 18-O-lower alkyl-lO-methoxy-3-oxo-2,3-sec0- deserpidates,

e.g. methyl IO-methoxy-l8-O-methyl-3-oxo-2,3-seco-deserpidate,

methyl 18-O-ethyl-10-methoxy-3-oxo-2,3 seco deserpidate,

methyl IO-methoxy-l8-O-n-propyl-3-oxo-2,3seco-deserpidate,

ethyl 10-methoxy-18-O-methyl-3 -oxo-2,3 seco deserpidate,

n-propyl IO-methoxy-l8-O-methyl-3-oxo-2,3-seco-deserpidate,

isopropyl IO-methoxy- 1 8-O-methyl-3 -oxo-2,3 -seco-d eserpidate and the like,

lower alkyl ll-ethoxy-lS-O-lower alkyl-3-oxo-2,3secodeserpidates,

e.g. methyl 11-ethoxy-l8-O-methyl-3-oxo-2,3-seco-deserpidate,

methyl 1 1-ethoxy-18-O-ethyl-3 -oxo-2,3-seco deserpidate and the like,

lower alkyl 18-O-1ower alkyl-l1-n-propyloxy-3-oxo-2,3-

seco-deserpidates,

e.g. methyl IS-O-methyl-l l-n-propyloxy-3-oxo-2,3secodeserpidate,

methyl IS-O-ethyl-l 1-n-propyloxy-3-oxo-2,3-seco-deserpidate and the like,

lower alkyl 1l-isopropyloxy-l8-O-lower alkyl-3-oxo-2,3-

seco-deserpidates,

e.g. methyl 1l-isopropyloxy-l8-O-methyl-3 -oxo-2,3-secodeserpidate,

ethyl ll-isopropyloxy-18-O-methyl-3-oxo-2,3-seco deserpidate and the like,

lower alkyl ll-n-butyloxy-18-O-lower alkyl 3 oxo 2,3-

seco-deserpidates,

e.g. methyl 1l-n-butyloxy-l8-O-methyl-3-oxo-2,3-seco-deserpidate,

methyl 1l-n-butyloxy-18-O-ethyl-3-oxo-2,3-seco deserpidate and the like,

lower alkyl l8-O-lower alkyl-12-methoxy-3-oxo-2,3-secodeserpidates,

e.g. methyl l2-methoxy-18-O-methyl-3-oxo-2,3-seco-deserpidate,

ethyl 12-methoxy-l8-O-methyl-3-oxo-2,3-seco-deserpidate and the like.

An additional preferred group of compounds is represented by the lower alkyl 18-O-lower alkyl-3-oxo-2,3-secodeserpidates, in which lower alkyl contains preferably from one to four carbon atoms, and is represented primarily by methyl, as well as ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like. Specific members of this group are, for example,

methyl 18-O-methyl-3-oxo-2,3-seco-deserpidate, methyl l8-O-ethyl-3 -oxo-2,3-seco-deserpidate, methyl 18-O-n-propyl-3-oxo-2,3-seco-deserpidate, methyl l8-O-isopropyl-3 -oxo-2,3 seco-deserpidate, ethyl 18-O-methyl-3 -oxo-2,3 -seco-deserpidate, n-propyl l8-O-ethyl-3-oxo-2,3-seco-deserpidate, isopropyl 18-O-methyl-3-oxo-2,3-seco-deserpidate, and

the like.

Another preferred group of these intermediates is represented by the formula: 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 